2024/10/07 更新

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写真a

ナガサキ マサオ
長﨑 正朗
NAGASAKI MASAO
所属
生体防御医学研究所 附属高深度オミクスサイエンスセンター 教授
生体防御医学研究所 附属高深度オミクスサイエンスセンター(併任)
システム生命科学府 システム生命科学専攻(併任)
医学系学府 医科学専攻(併任)
職名
教授
電話番号
0926424815
プロフィール
生体防御医学研究所附属高深度オミクスサイエンスセンターに所属し、バイオメディカル情報解析分野を主宰している。
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研究分野

  • ライフサイエンス / ゲノム生物学

研究テーマ・研究キーワード

  • 研究テーマ: 大規模情報解析

    研究キーワード: 大規模情報解析

    研究期間: 2024年

  • 研究テーマ: バイオメディカルインフォマティクス

    研究キーワード: バイオメディカルインフォマティクス

    研究期間: 2024年

  • 研究テーマ: バイオインフォマティクス

    研究キーワード: バイオインフォマティクス

    研究期間: 2024年

  • 研究テーマ: ヒトを中心としたゲノム、オミクス情報、また、臨床情報の大規模情報について情報解析を展開できる次世代かつ即戦力となるデータサイエンス時代の人材を育成

    研究キーワード: バイオインフォマティクス、メディカルインフォマティクス、大規模情報解析

    研究期間: 2023年4月

受賞

  • 最優秀論文賞

    2017年8月   情報処理学会DICOMO2017実行委員会   プライバシ保護ゲノム解析のための秘密計算フィッシャー正確検定の実装評価

  • IEEE BioVis 2011 Contest Award

    2011年10月   IEEE (The Institute of Electrical and Electronics Engineers, Inc.)  

論文

  • Mutations of CYP1B1 and FOXC1 genes for childhood glaucoma in Japanese individuals 査読

    Fuse N., Kimura M., Shimizu A., Koshiba S., Hamanaka T., Nakamura M., Ishida N., Sakai H., Ikeda Y., Mori K., Endo A., Nagasaki M., Katsuoka F., Yasuda J., Matsubara Y., Nakazawa T., Yamamoto M.

    Japanese Journal of Ophthalmology   2024年8月   ISSN:0021-5155

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Journal of Ophthalmology  

    Purpose: To explore the frequency and positions of genetic mutations in CYP1B1 and FOXC1 in a Japanese population. Study design: Molecular genetic analysis. Methods: Genomic DNA was extracted from 31 Japanese patients with childhood glaucoma (CG) from 29 families. We examined the CYP1B, FOXC1, and MYOC genes using Sanger sequencing and whole-exome sequencing (WES). Results: For CYP1B1, we identified 9 families that harbored novel mutations, p.A202T, p.D274E, p.Q340*, and p.V420G; the remaining mutations had been previously reported. When mapped to the CYP1B1 protein structure, all mutations appeared to influence the enzymatic activity of CYP1B1 by provoking structural deformity. Five patients were homozygotes or compound heterozygotes, supporting the recessive inheritance of the CYP1B1 mutations in CG. In contrast, four patients were heterozygous for the CYP1B1 mutation, suggesting the presence of regulatory region mutations or strong modifiers. For the FOXC1 gene, we identified 3 novel mutations, p.Q23fs, p.Q70R, and p.E163*, all of which were identified in a heterozygous state. No mutation was found in the MYOC gene in these CG patients. All individuals with CYP1B1 and FOXC1 mutations were severely affected by early-onset CG. In the CYP1B1-, FOXC1-, and MYOC-negative families, we also searched for variants in the other candidate genes reported for CG through WES, but could not find any mutations in these genes. Conclusions: Our analyses of 29 CG families revealed 9 families with point mutations in the CYP1B1 gene, and four of those patients appeared to be heterozygotes, suggesting the presence of complex pathogenic mechanisms. FOXC1 appears to be another major causal gene of CG, indicating that panel sequencing of CYP1B1 and FOXC1 will be useful for diagnosis of CG in Japanese individuals.

    DOI: 10.1007/s10384-024-01103-0

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  • Genetically Predicted Higher Levels of Caffeic Acid Are Protective Against Ulcerative Colitis: A Comprehensive Metabolome Analysis 査読

    Naito, T; Osaka, R; Kakuta, Y; Kawai, Y; Khor, SS; Umeno, J; Tokunaga, K; Nagai, H; Shimoyama, Y; Moroi, R; Shiga, H; Nagasaki, M; Kinouchi, Y; Masamune, A

    INFLAMMATORY BOWEL DISEASES   2024年6月   ISSN:1078-0998 eISSN:1536-4844

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    記述言語:英語  

    DOI: 10.1093/ibd/izae143

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  • Identification of the hybrid gene <i>LILRB5-3</i> by long-read sequencing and implication of its novel signaling function 査読

    Hirayasu, K; Khor, SS; Kawai, Y; Shimada, M; Omae, Y; Hasegawa, G; Hashikawa, Y; Tanimoto, H; Ohashi, J; Hosomichi, K; Tajima, A; Nakamura, H; Nakamura, M; Tokunaga, K; Hanayama, R; Nagasaki, M

    FRONTIERS IN IMMUNOLOGY   15   1398935   2024年5月   ISSN:1664-3224

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    記述言語:英語   出版者・発行元:Frontiers in Immunology  

    Leukocyte immunoglobulin (Ig)-like receptors (LILRs) on human chromosome 19q13.4 encode 11 immunoglobulin superfamily receptors, exhibiting genetic diversity within and between human populations. Among the LILR genes, the genomic region surrounding LILRB3 and LILRA6 has yet to be fully characterized due to their significant sequence homology, which makes it difficult to differentiate between them. To examine the LILRB3 and LILRA6 genomic region, a tool named JoGo-LILR CN Caller, which can call copy number from short-read whole genome sequencing (srWGS) data, was applied to an extensive international srWGS dataset comprising 2,504 samples. During this process, a previously unreported loss of both LILRB3 and LILRA6 was detected in three samples. Using long-read sequencing of these samples, we have discovered a novel large deletion (33,692 bp) in the LILRB3 and LILRA6 genomic regions in the Japanese population. This deletion spanned three genes, LILRB3, LILRA6, and LILRB5, resulting in LILRB3 exons 12-13 being located immediately downstream of LILRB5 exons 1-12 with the loss of LILRA6, suggesting the potential expression of a hybrid gene between LILRB5 and LILRB3 (LILRB5-3). Transcription and subsequent translation of the LILRB5-3 hybrid gene were also verified. The hybrid junction was located within the intracellular domain, resulting in an LILRB5 extracellular domain fused to a partial LILRB3 intracellular domain with three immunoreceptor tyrosine-based inhibitory motifs (ITIMs), suggesting that LILRB5-3 acquired a novel signaling function. Further application of the JoGo-LILR tool to srWGS samples suggested the presence of the LILRB5-3 hybrid gene in the CEU population. Our findings provide insight into the genetic and functional diversity of the LILR family.

    DOI: 10.3389/fimmu.2024.1398935

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  • Precise immunofluorescence canceling for highly multiplexed imaging to capture specific cell states 査読

    Tomimatsu, K; Fujii, T; Bise, R; Hosoda, K; Taniguchi, Y; Ochiai, H; Ohishi, H; Ando, K; Minami, R; Tanaka, K; Tachibana, T; Mori, S; Harada, A; Maehara, K; Nagasaki, M; Uchida, S; Kimura, H; Narita, M; Ohkawa, Y

    NATURE COMMUNICATIONS   15 ( 1 )   3657   2024年5月   eISSN:2041-1723

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    記述言語:英語   出版者・発行元:Nature Communications  

    Cell states are regulated by the response of signaling pathways to receptor ligand-binding and intercellular interactions. High-resolution imaging has been attempted to explore the dynamics of these processes and, recently, multiplexed imaging has profiled cell states by achieving a comprehensive acquisition of spatial protein information from cells. However, the specificity of antibodies is still compromised when visualizing activated signals. Here, we develop Precise Emission Canceling Antibodies (PECAbs) that have cleavable fluorescent labeling. PECAbs enable high-specificity sequential imaging using hundreds of antibodies, allowing for reconstruction of the spatiotemporal dynamics of signaling pathways. Additionally, combining this approach with seq-smFISH can effectively classify cells and identify their signal activation states in human tissue. Overall, the PECAb system can serve as a comprehensive platform for analyzing complex cell processes.

    DOI: 10.1038/s41467-024-47989-9

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  • A genome-wide association study identified <i>PTPN2</i> as a population-specific susceptibility gene locus for primary biliary cholangitis 査読 国際誌

    Hitomi, Y; Ueno, K; Aiba, Y; Nishida, N; Kono, M; Sugihara, M; Kawai, Y; Kawashima, M; Khor, SS; Sugi, K; Kouno, H; Kouno, H; Naganuma, A; Iwamoto, S; Katsushima, S; Furuta, K; Nikami, T; Mannami, T; Yamashita, T; Ario, K; Komatsu, T; Makita, F; Shimada, M; Hirashima, N; Yokohama, S; Nishimura, H; Sugimoto, R; Komura, T; Ota, H; Kojima, M; Nakamuta, M; Fujimori, N; Yoshizawa, K; Mano, Y; Takahashi, H; Hirooka, K; Tsuruta, S; Sato, T; Yamasaki, K; Kugiyama, Y; Motoyoshi, Y; Suehiro, T; Saeki, A; Matsumoto, K; Nagaoka, S; Abiru, S; Yatsuhashi, H; Ito, M; Kawata, K; Takaki, A; Arai, K; Arinaga, T; Abe, M; Harada, M; Taniai, M; Zeniya, M; Ohira, H; Shimoda, S; Komori, A; Tanaka, A; Ishigaki, K; Nagasaki, M; Tokunaga, K; Nakamura, M

    HEPATOLOGY   80 ( 4 )   776 - 790   2024年4月   ISSN:0270-9139 eISSN:1527-3350

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND AIMS: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-non-specific) and non-shared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC. APPROACH RESULTS: Protein tyrosine phosphatase non-receptor type 2 (PTPN2) was identified as a novel PBC susceptibility gene locus through a GWAS and subsequent genome-wide meta-analysis involving 2,181 cases and 2,699 controls from the Japanese population (GWAS-lead variant: rs8098858, p=2.6×10-8). In-silico and in-vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells (Tfh) and plasmacytoid dendritic cells (pDCs). Infiltration of PTPN2-positive T-cells and pDCs were confirmed in the portal area of the PBC-liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in-vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758. CONCLUSIONS: PTPN2, a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC via an insufficient negative feedback loop caused by the PTPN2 risk allele of rs2292758 in IFN signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.

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  • rs10924104 in the expression enhancer motif of CD58 confers susceptibility to human autoimmune diseases 査読 国際誌

    Hitomi, Y; Ueno, K; Aiba, Y; Nishida, N; Kawai, Y; Kawashima, M; Khor, SS; Takada, S; Iwabuchi, C; Nagasaki, M; Tokunaga, K; Nakamura, M

    HUMAN GENETICS   143 ( 1 )   19 - 33   2024年1月   ISSN:0340-6717 eISSN:1432-1203

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Human Genetics  

    CD58 plays roles in cell adhesion and co-stimulation with antigen presentation from major histocompatibility complex class II on antigen-presenting cells to T-cell antigen receptors on naïve T cells. CD58 reportedly contributes to the development of various human autoimmune diseases. Recently, genome-wide association studies (GWASs) identified CD58 as a susceptibility locus for autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and primary biliary cholangitis (PBC). However, the primary functional variant and molecular mechanisms of susceptibility to autoimmune diseases in the CD58 locus were not clarified. Here, rs10924104, located in the ZNF35-binding motif within the gene expression regulatory motif, was identified as the primary functional variant for SLE, MS, and PBC among genetic variants showing stronger linkage disequilibrium (LD) with GWAS-lead variants in the CD58 locus. Expression-quantitative trait locus (e-QTL) data for each distinct blood cell type and in vitro functional analysis using the CRISPR/Cas9 system corroborated the functional role of rs10924104 in the upregulation of CD58 transcription by the disease-risk allele. Additionally, the strength of disease susceptibility observed in the CD58 locus could be accounted for by the strength of LD between rs10924104 and each GWAS-lead variant. In conclusion, the present study demonstrated for the first time the existence of a shared autoimmune disease-related primary functional variant (i.e., rs10924104) that regulates the expression of CD58. Clarifying the molecular mechanism of disease susceptibility derived from such a shared genetic background is important for understanding human autoimmune diseases and human immunology.

    DOI: 10.1007/s00439-023-02617-2

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  • High-risk pathogenic germline variants in blood relatives of BRCA1/2 negative probands 査読

    Yoshida R., Kaneyasu T., Ueki A., Yamauchi H., Ohsumi S., Ohno S., Aoki D., Baba S., Kawano J., Matsumoto N., Nagasaki M., Ueno T., Inari H., Kobayashi Y., Takei J., Gotoh O., Nishi M., Okamura M., Kaneko K., Okawa M., Suzuki M., Amino S., Inuzuka M., Noda T., Mori S., Nakamura S.

    Breast Cancer   2024年   ISSN:13406868

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    出版者・発行元:Breast Cancer  

    Background: Tailored, preventive cancer care requires the identification of pathogenic germline variants (PGVs) among potentially at-risk blood relatives (BRs). Cascade testing is carried out for BRs of probands who are positive for PGVs of an inherited cancer but not for negative probands. This study was conducted to examine the prevalence of PGVs for BRs of PGV-negative probands. Methods: PGV prevalence was assessed for 682 BRs of 281 probands with BRCA1/BRCA2 wild-type hereditary breast and ovarian cancer (HBOC) syndrome. Results: PGVs were discovered in 22 (45.8%) of the 48 BRs of the PGV-positive probands and in 14 (2.2%) of 634 BRs of the PGV-negative probands. Eleven PGVs on high-risk BRCA1, BRCA2, and TP53 genes were present only in BRs and not in the probands (probands vs BRs in Fisher exact test; p = 0.0104; odds ratio [OR] = 0.000 [0.000–0.5489 of 95% confidence interval]), partly due to the nature of the selection criteria. The enrichment of high-risk PGVs among BRs was also significant as compared with a non-cancer East Asian population (p = 0.0016; OR = 3.0791 [1.5521–5.6694]). PGV prevalence, risk class of gene, and genotype concordance were unaffected by the cancer history among BRs. Conclusion: These findings imply the necessity to construct a novel testing scheme to complement cascade testing.

    DOI: 10.1007/s12282-024-01615-0

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  • Analysis of Genetic Polymorphism of Bitter Taste Receptor TAS2R38 and TAS2R46, and Its Relationship with Eating and Drinking Habits in Japanese ToMMo Subjects 招待 査読 国際誌

    M. Yamaki, H. Saito, T. Mimori, Y. Suzuki, M. Nagasaki, K. Suzuki, S. Satoh-Kuriwada, N. Shoji, K. Isono, T. Goto, H. Shirakawa, M. Komai

    J Nutr Sci Vitaminol   2023年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

  • The Results of Genetic Analysis and Clinical Outcomes after Stent Deployment in Adult Patients with Isolated Peripheral Pulmonary Artery Stenosis 招待 査読 国際誌

    M. Kanezawa, H. Shimokawahara, M. Tsuji, K. Suruga, A. Miyagi, M. Marunaka, T. Mukai, T. Kawaguchi, T.Y. Yang, I. Yamaguchi, M. Nagasaki, F. Matsuda, H. Matsubara

    Eur Respir J   2023年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    The Results of Genetic Analysis and Clinical Outcomes after Stent Deployment in Adult Patients with Isolated Peripheral Pulmonary Artery Stenosisの論文がEuropean respriratory journalに掲載された。

  • 抗原提示補助シグナル分子の遺伝的バリアントに起因する自己免疫疾患感受性の分子機序の解明

    人見 祐基, 植野 和子, 相葉 佳洋, 西田 奈央, 河合 洋介, 川嶋 実苗, Khor Seik-Soon, 長崎 正朗, 徳永 勝士, 中村 稔

    MHC: Major Histocompatibility Complex   30 ( 2Suppl. )   83 - 83   2023年9月   ISSN:2186-9995 eISSN:2187-4239

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    記述言語:日本語   出版者・発行元:(一社)日本組織適合性学会  

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  • HLA-DQA1*05 and upstream variants of PPARGC1B are associated with infliximab persistence in Japanese Crohn's disease patients 査読 国際誌

    Shimoda, F; Naito, T; Kakuta, Y; Kawai, Y; Tokunaga, K; NCBN Controls WGS Consortium; Shimoyama, Y; Moroi, R; Shiga, H; Nagasaki, M; Kinouchi, Y; Masamune, A; Ishibashi-Ueda, H; Tomita, T; Noguchi, M; Takahashi, A; Goto, YI; Yoshida, S; Hattori, K; Matsumura, R; Iida, A; Maruoka, Y; Gatanaga, H; Sugiyama, M; Suzuki, S; Miyo, K; Matsubara, Y; Umezawa, A; Hata, K; Kaname, T; Ozaki, K; Tokuda, H; Watanabe, H; Niida, S; Noiri, E; Kitajima, K; Omae, Y; Miyahara, R; Shimanuki, H; Kawai, Y; Tokunaga, K

    PHARMACOGENOMICS JOURNAL   23 ( 6 )   141 - 148   2023年7月   ISSN:1470-269X eISSN:1473-1150

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pharmacogenomics Journal  

    Recently, the HLA-DQA1*05 (rs2097432) genetic variation has been reported to be linked to early infliximab (IFX) treatment failure in the Caucasian Crohn's disease (CD) population, but that evidence is scarce in the Asian population. This study aimed to investigate the relationship between rs2097432 and the cumulative discontinuation-free time of IFX (IFX persistence) in 189 Japanese biologics-naive CD patients. We also performed a genome-wide association study (GWAS) to discover novel genetic predictors for IFX persistence. The C allele of rs2097432 significantly increased the risk of early discontinuation of IFX [Hazard ratio (HR) = 2.23 and P-value = 0.026]. In GWAS, one locus tagged by rs73277969, located upstream of PPARGC1B which attenuates macrophage-mediated inflammation, reached genome-wide significance (HR = 6.04 and P-value = 7.93E-9). Pathway analysis suggested association of signaling by PDGF and FCGR activation signaling with IFX persistence (P-value = 8.56E-5 and 5.80E-4, respectively).

    DOI: 10.1038/s41397-023-00312-z

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  • Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries 査読 国際誌

    Liu, ZJ; Liu, RZ; Gao, H; Jung, S; Gao, X; Sun, RC; Liu, XM; Kim, Y; Lee, HS; Kawai, Y; Nagasaki, M; Umeno, J; Tokunaga, K; Kinouchi, Y; Masamune, A; Shi, WZ; Shen, CG; Guo, ZL; Yuan, K; Zhu, S; Li, DL; Liu, JJ; Ge, T; Cho, J; Daly, MJ; McGovern, DPB; Ye, BD; Song, K; Kakuta, Y; Li, MS; Huang, HL; Abreu, M; Achkar, JP; Andersen, V; Bernstein, C; Brant, SR; Bujanda, L; Ng, SC; Cho, J; Daly, MJ; Denson, LA; Duerr, RH; Ferguson, LR; Franchimont, D; Franke, A; Gearry, R; Hakonarson, H; Halfvarson, J; Heller, C; Huang, HL; Julià, A; Kelsen, J; Khalili, H; Kugathasan, S; Kupcinskas, J; Latiano, A; Louis, E; Malekzadeh, R; McCauley, JL; McGovern, DPB; Moran, C; Okou, D; Orchard, T; Palotie, A; Parkes, M; Pekow, J; Potocnik, U; Radford-Smith, G; Rioux, JD; Rogler, G; Sands, B; Silverberg, M; Sokol, H; Vermeire, S; Weersma, RK; Xavier, RJ; Hu, NZ; Cao, Q; Wang, YF; Miao, YL; Zhang, HJ; Lv, XP; Gao, X; Zhang, H; Su, JL; Feng, BS; Zhao, Y; Zhu, LR; Chen, Y; Zhu, LX; Chen, CX; Wang, YL; Wang, YD; Pang, Z; Chen, YX; Zhang, XL; Li, H; Yu, Q; Ye, M; Zhang, SM; Tang, W; Wang, M; Cao, XC; Zhu, RX; Zhou, GX; Bian, ZL; Guo, XF; Wu, XL; Liu, JC; Xu, W; Li, YQ; Guo, Q; Guo, ZG; Li, MS; Liu, ZJ

    NATURE GENETICS   55 ( 5 )   796 - 806   2023年5月   ISSN:1061-4036 eISSN:1546-1718

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nature Genetics  

    Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestriesの論文がNature Geneticsに掲載された。

    DOI: 10.1038/s41588-023-01384-0

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  • Novel HLA allele associations with susceptibility, staging, symptomatic state, autoimmune hepatitis and hepatocellular carcinoma events for primary biliary cholangitis in the Japanese population 査読 国際誌

    Khor, SS; Ueno, K; Nishida, N; Kawashima, M; Kawai, Y; Aiba, Y; Hitomi, Y; Nagasaki, M; Nakamura, M; Tokunaga, K

    FRONTIERS IN IMMUNOLOGY   14   1151502 - 1151502   2023年5月   ISSN:1664-3224

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Frontiers in Immunology  

    Primary biliary cholangitis (PBC) is a rare autoimmune disease with a clear predisposition for human leukocyte antigen (HLA)-DR/DQ-associated loss of immune tolerance for the E2 component of the pyruvate dehydrogenase complex. Three-field-resolution HLA imputation of 1,670 Japanese PBC patients and 2,328 healthy controls was conducted using Japanese population-specific HLA reference panels. Eighteen previously reported Japanese PBC-associated HLA alleles were confirmed and extended to 3-field-resolution, including HLA-DRB1*08:03 to HLA-DRB1*08:03:02, HLA-DQB1*03:01 to HLA-DQB1*03:01:01, HLA-DQB1*04:01 to HLA-DQB1*04:01:01 and HLA-DQB1*06:04 to HLA-DQB1*06:04:01. In addition, additional significant novel HLA alleles were identified, including 3 novel susceptible HLA-DQA1 alleles: HLA-DQA1*03:03:01, HLA-DQA1*04:01:01, HLA-DQA1*01:04:01 and 1 novel protective HLA-DQA1 allele, HLA-DQA1*05:05:01. In addition, PBC patients carrying HLA-DRB1*15:01:01 and HLA-DQA1*03:03:01 would have a higher predisposition toward developing concomitant autoimmune hepatitis (AIH). Further, late-stage and symptomatic PBC shared the same susceptible HLA alleles of HLA-A*26:01:01, HLA-DRB1*09:01:02 and HLA-DQB1*03:03:02. Lastly, HLA-DPB1*05:01:01 was identified as a potential risk HLA allele for development of hepatocellular carcinoma (HCC) in PBC patients. In conclusion, we have extended the current knowledge of HLA allele associations to 3-field resolution and identified novel HLA allele associations with predisposition risk, staging, symptomatic state, and AIH and HCC events for Japanese PBC patients.

    DOI: 10.3389/fimmu.2023.1151502

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  • Prediction Model with HLA-A*33:03 Reveals Number of Days to Develop Liver Cancer from Blood Test 査読 国際誌

    Nishida, N; Ohashi, J; Suda, G; Chiyoda, T; Tamaki, N; Tomiyama, T; Ogasawara, S; Sugiyama, M; Kawai, Y; Khor, SS; Nagasaki, M; Fujimoto, A; Tsuchiura, T; Ishikawa, M; Matsuda, K; Yano, H; Yoshizumi, T; Izumi, N; Hasegawa, K; Sakamoto, N; Mizokami, M; Tokunaga, K

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   24 ( 5 )   2023年3月   ISSN:16616596 eISSN:1422-0067

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Molecular Sciences  

    The development of liver cancer in patients with hepatitis B is a major problem, and several models have been reported to predict the development of liver cancer. However, no predictive model involving human genetic factors has been reported to date. For the items incorporated in the prediction model reported so far, we selected items that were significant in predicting liver carcinogenesis in Japanese patients with hepatitis B and constructed a prediction model of liver carcinogenesis by the Cox proportional hazard model with the addition of Human Leukocyte Antigen (HLA) genotypes. The model, which included four items-sex, age at the time of examination, alpha-fetoprotein level (log10AFP) and presence or absence of HLA-A*33:03-revealed an area under the receiver operating characteristic curve (AUROC) of 0.862 for HCC prediction within 1 year and an AUROC of 0.863 within 3 years. A 1000 repeated validation test resulted in a C-index of 0.75 or higher, or sensitivity of 0.70 or higher, indicating that this predictive model can distinguish those at high risk of developing liver cancer within a few years with high accuracy. The prediction model constructed in this study, which can distinguish between chronic hepatitis B patients who develop hepatocellular carcinoma (HCC) early and those who develop HCC late or not, is clinically meaningful.

    DOI: 10.3390/ijms24054761

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  • Genome-Wide Association Study and Transcriptome of Japanese Patients with Developmental Dysplasia of the Hip Demonstrates an Association with the Ferroptosis Signaling Pathway 査読

    Mori Y., Ueno K., Chiba D., Hashimoto K., Kawai Y., Baba K., Tanaka H., Aki T., Ogasawara M., Shibasaki N., Tokunaga K., Aizawa T., Nagasaki M.

    International Journal of Molecular Sciences   24 ( 5 )   5019 - 5019   2023年3月   ISSN:16616596 eISSN:1422-0067

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    記述言語:その他   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Molecular Sciences  

    This study examined the association between developmental dysplasia of the hip (DDH) and disease-associated loci in a Japanese cohort. A genome-wide association study (GWAS) of 238 Japanese patients with DDH and 2044 healthy individuals was performed. As a replicate, GWAS was also conducted on the UK Biobank data with 3315 cases and matched 74,038 controls. Gene set enrichment analyses (GSEAs) of both the genetics and transcriptome of DDH were performed. Transcriptome analysis of cartilage specimens from DDH-associated osteoarthritis and femoral neck fractures was performed as a control. Most of the lead variants were very low-frequency ones in the UK, and variants in the Japanese GWAS could not be replicated with the UK GWAS. We assigned DDH-related candidate variants to 42 and 81 genes from the Japanese and UK GWASs, respectively, using functional mapping and annotation. GSEA of gene ontology, disease ontology, and canonical pathways identified the most enriched pathway to be the ferroptosis signaling pathway, both in the Japanese gene set as well as the Japanese and UK merged set. Transcriptome GSEA also identified significant downregulation of genes in the ferroptosis signaling pathway. Thus, the ferroptosis signaling pathway may be associated with the pathogenic mechanism of DDH.

    DOI: 10.3390/ijms24055019

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  • CFH-CFHR1 hybrid genes in two cases of atypical hemolytic uremic syndrome 査読

    Sugawara Y., Kato H., Nagasaki M., Yoshida Y., Fujisawa M., Minegishi N., Yamamoto M., Nangaku M.

    Journal of Human Genetics   68 ( 6 )   427 - 430   2023年2月   ISSN:1434-5161 eISSN:1435-232X

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    記述言語:その他   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Human Genetics  

    Abstract

    Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated disease that manifests as the triad of thrombotic microangiopathy. We identified two aHUS patients with neither anti-complement factor H (CFH) antibodies nor causative variants of seven aHUS-related genes (CFH, CFI, CFB, C3, MCP, THBD, and DGKE); however, their plasma showed increased levels of hemolysis by hemolytic assay, which strongly suggests CFH-related abnormalities. Using a copy number variation (CNV) analysis of the CFH/CFHR gene cluster, we identified CFH-CFHR1 hybrid genes in these patients. We verified the absence of aHUS-related abnormal CNVs of the CFH gene in control genomes of 2036 individuals in the general population, which suggests that pathogenicity is related to these hybrid genes. Our study emphasizes that, for patients suspected of having aHUS, it is important to perform an integrated analysis based on a clinical examination, functional analysis, and detailed genetic investigation.

    DOI: 10.1038/s10038-023-01129-1

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    その他リンク: https://www.nature.com/articles/s10038-023-01129-1

  • Design and implementation of a hybrid cloud system for large-scale human genomic research 査読 国際誌

    Masao Nagasaki, Yayoi Sekiya, Akihiro Asakura, Ryo Teraoka, Ryoko Otokozawa, Hiroki Hashimoto, Takahisa Kawaguchi, Keiichiro Fukazawa, Yuichi Inadomi, Ken T. Murata, Yasuyuki Ohkawa, Izumi Yamaguchi, Takamichi Mizuhara, Katsushi Tokunaga, Yuji Sekiya, Toshihiro Hanawa, Ryo Yamada, Fumihiko Matsuda

    Human Genome Variation   10 ( 1 )   6 - 6   2023年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    <jats:title>Abstract</jats:title><jats:p>In the field of genomic medical research, the amount of large-scale information continues to increase due to advances in measurement technologies, such as high-performance sequencing and spatial omics, as well as the progress made in genomic cohort studies involving more than one million individuals. Therefore, researchers require more computational resources to analyze this information. Here, we introduce a hybrid cloud system consisting of an on-premise supercomputer, science cloud, and public cloud at the Kyoto University Center for Genomic Medicine in Japan as a solution. This system can flexibly handle various heterogeneous computational resource-demanding bioinformatics tools while scaling the computational capacity. In the hybrid cloud system, we demonstrate the way to properly perform joint genotyping of whole-genome sequencing data for a large population of 11,238, which can be a bottleneck in sequencing data analysis. This system can be one of the reference implementations when dealing with large amounts of genomic medical data in research centers and organizations.</jats:p>

    DOI: 10.1038/s41439-023-00231-2

  • Secure secondary utilization system of genomic data using quantum secure cloud 査読

    Fujiwara M., Hashimoto H., Doi K., Kujiraoka M., Tanizawa Y., Ishida Y., Sasaki M., Nagasaki M.

    Scientific Reports   12 ( 1 )   2022年12月

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    出版者・発行元:Scientific Reports  

    Secure storage and secondary use of individual human genome data is increasingly important for genome research and personalized medicine. Currently, it is necessary to store the whole genome sequencing information (FASTQ data), which enables detections of de novo mutations and structural variations in the analysis of hereditary diseases and cancer. Furthermore, bioinformatics tools to analyze FASTQ data are frequently updated to improve the precision and recall of detected variants. However, existing secure secondary use of data, such as multi-party computation or homomorphic encryption, can handle only a limited algorithms and usually requires huge computational resources. Here, we developed a high-performance one-stop system for large-scale genome data analysis with secure secondary use of the data by the data owner and multiple users with different levels of data access control. Our quantum secure cloud system is a distributed secure genomic data analysis system (DSGD) with a “trusted server” built on a quantum secure cloud, the information-theoretically secure Tokyo QKD Network. The trusted server will be capable of deploying and running a variety of sequencing analysis hardware, such as GPUs and FPGAs, as well as CPU-based software. We demonstrated that DSGD achieved comparable throughput with and without encryption on the trusted server Therefore, our system is ready to be installed at research institutes and hospitals that make diagnoses based on whole genome sequencing on a daily basis.

    DOI: 10.1038/s41598-022-22804-x

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  • Sex-Specific Differences in the Transcriptome of the Human Dorsolateral Prefrontal Cortex in Schizophrenia 査読 国際誌

    Yu Z., Ueno K., Funayama R., Sakai M., Nariai N., Kojima K., Kikuchi Y., Li X., Ono C., Kanatani J., Ono J., Iwamoto K., Hashimoto K., Kinoshita K., Nakayama K., Nagasaki M., Tomita H.

    Molecular Neurobiology   60 ( 2 )   1083 - 1098   2022年11月   ISSN:08937648

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Molecular Neurobiology  

    Schizophrenia presents clinical and biological differences between males and females. This study investigated transcriptional profiles in the dorsolateral prefrontal cortex (DLPFC) using postmortem data from the largest RNA-sequencing (RNA-seq) database on schizophrenic cases and controls. Data for 154 male and 113 female controls and 160 male and 93 female schizophrenic cases were obtained from the CommonMind Consortium. In the RNA-seq database, the principal component analysis showed that sex effects were small in schizophrenia. After we analyzed the impact of sex-specific differences on gene expression, the female group showed more significantly changed genes compared with the male group. Based on the gene ontology analysis, the female sex-specific genes that changed were overrepresented in the mitochondrion, ATP (phosphocreatine and adenosine triphosphate)-, and metal ion-binding relevant biological processes. An ingenuity pathway analysis revealed that the differentially expressed genes related to schizophrenia in the female group were involved in midbrain dopaminergic and γ-aminobutyric acid (GABA)-ergic neurons and microglia. We used methylated DNA-binding domain-sequencing analyses and microarray to investigate the DNA methylation that potentially impacts the sex differences in gene transcription using a maternal immune activation (MIA) murine model. Among the sex-specific positional genes related to schizophrenia in the PFC of female offspring from MIA, the changes in the methylation and transcriptional expression of loci ACSBG1 were validated in the females with schizophrenia in independent postmortem samples by real-time PCR and pyrosequencing. Our results reveal potential genetic risks in the DLPFC for the sex-dependent prevalence and symptomology of schizophrenia.

    DOI: 10.1007/s12035-022-03109-6

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  • rs2013278 in the multiple immunological-trait susceptibility locus CD28 regulates the production of non-functional splicing isoforms 査読 国際誌

    Hitomi Y., Aiba Y., Ueno K., Nishida N., Kawai Y., Kawashima M., Tsuiji M., Iwabuchi C., Takada S., Miyake N., Nagasaki M., Tokunaga K., Nakamura M.

    Human Genomics   16 ( 1 )   46 - 46   2022年10月   ISSN:14739542

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Human Genomics  

    BACKGROUND: Ligation of CD28 with ligands such as CD80 or CD86 provides a critical second signal alongside antigen presentation by class II major histocompatibility complex expressed on antigen-presenting cells through the T cell antigen receptor for naïve T cell activation. A number of studies suggested that CD28 plays an important role in the pathogenesis of various human diseases. Recent genome-wide association studies (GWASs) identified CD28 as a susceptibility locus for lymphocyte and eosinophil counts, multiple sclerosis, ulcerative colitis, celiac disease, rheumatoid arthritis, asthma, and primary biliary cholangitis. However, the primary functional variant and molecular mechanisms of disease susceptibility in this locus remain to be elucidated. This study aimed to identify the primary functional variant from thousands of genetic variants in the CD28 locus and elucidate its functional effect on the CD28 molecule. RESULTS: Among the genetic variants exhibiting stronger linkage disequilibrium (LD) with all GWAS-lead variants in the CD28 locus, rs2013278, located in the Rbfox binding motif related to splicing regulation, was identified as a primary functional variant related to multiple immunological traits. Relative endogenous expression levels of CD28 splicing isoforms (CD28i and CD28Δex2) compared with full-length CD28 in allele knock-in cell lines generated using CRISPR/Cas9 were directly regulated by rs2013278 (P < 0.05). Although full-length CD28 protein expressed on Jurkat T cells showed higher binding affinity for CD80/CD86, both CD28i and CD28Δex2 encoded loss-of-function isoforms. CONCLUSION: The present study demonstrated for the first time that CD28 has a shared disease-related primary functional variant (i.e., rs2013278) that regulates the CD28 alternative splicing that generates loss-of-function isoforms. They reduce disease risk by inducing anergy of effector T cells that over-react to autoantigens and allergens.

    DOI: 10.1186/s40246-022-00419-7

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  • 原発性胆汁性胆管炎の肝組織におけるPOU2AF1とその関連遺伝子の解析

    相葉 佳洋, 伊東 正博, 植野 和子, 人見 祐基, 小森 敦正, 阿比留 正剛, 長岡 進矢, 八橋 弘, 長崎 正朗, 徳永 勝士, 中村 稔

    日本臨床免疫学会総会プログラム・抄録集   50回   109 - 109   2022年10月

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    記述言語:日本語   出版者・発行元:(一社)日本臨床免疫学会  

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  • Genome-wide Survival Analysis for Macular Neovascularization Development in Central Serous Chorioretinopathy Revealed Shared Genetic Susceptibility with Polypoidal Choroidal Vasculopathy 査読 国際誌

    Mori Y., Miyake M., Hosoda Y., Miki A., Takahashi A., Muraoka Y., Miyata M., Sato T., Tamura H., Ooto S., Yamada R., Yamashiro K., Nakamura M., Tajima A., Nagasaki M., Honda S., Tsujikawa A.

    Ophthalmology   129 ( 9 )   1034 - 1042   2022年9月   ISSN:01616420

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Ophthalmology  

    PURPOSE: To identify susceptibility genes for macular neovascularization (MNV) development in central serous chorioretinopathy (CSC). DESIGN: Genome-wide survival analysis using a longitudinal cohort study. PARTICIPANTS: We included 402 and 137 patients with CSC but without MNV at their first visit from the Kyoto CSC Cohort and Kobe CSC dataset, respectively. All patients underwent detailed ophthalmologic examinations, including multimodal imaging, such as fundus autofluorescence, spectral-domain optical coherence tomography, and fluorescein angiography/indocyanine green angiography and/or optimal coherence tomography angiography. METHODS: We conducted a genome-wide survival analysis using the Kyoto CSC Cohort. We applied the Cox proportional hazard model to adjust for age, sex, and the first principal component. Single nucleotide polymorphisms (SNPs) with P-values <1.0×10-5 were carried forward to the replication in the Kobe CSC dataset. Moreover, we evaluated the contribution of previously-reported age-related macular degeneration (AMD) susceptibility loci. We used FUMA and ToppFun for the functional enrichment analysis. MAIN OUTCOME MEASURES: The association between SNPs and MNV development in patients with CSC. RESULTS: Rs370974631 near ARMS2 displayed a genome-wide significant association in the meta-analysis of discovery and replication result (hazard ratio [HR]meta = 3.63; Pmeta = 5.76×10-9). Among previously-reported AMD susceptibility loci, we additionally identified CFH rs800292 (HR = 0.39, P = 2.55×10-4), COL4A3 rs4276018 (HR = 0.26, P = 1.56×10-3), and B3GALTL rs9564692 (HR = 0.56, P = 8.30×10-3) as susceptibility loci for MNV development in CSC. The functional enrichment analysis revealed significant enrichment of eight pathways (GO:0051561, GO:0036444, GO:0008282, GO:1990246, GO:0015272, GO:0030955, GO:0031420, and GO:0005242) related to ion transport. CONCLUSIONS: ARMS2, CFH, COL4A3, and B3GALTL were identified as susceptibility genes for MNV development in CSC. The aforementioned four genes are known as susceptibility genes for AMD, whereas COL4A3 and B3GALTL were previously reported to be polypoidal choroidal vasculopathy (PCV)-specific susceptibility genes. Our findings revealed the shared genetic susceptibility between PCV and MNV secondary to CSC.

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  • Antiemetic effects of baclofen in a shrew model of postoperative nausea and vomiting: Whole‐transcriptome analysis in the nucleus of the solitary tract 査読 国際誌

    Daisuke Konno, Shigekazu Sugino, Tomoko F Shibata, Kazuharu Misawa, Yuka Imamura‐Kawasawa, Jun Suzuki, Kanta Kido, Masao Nagasaki, Masanori Yamauchi

    CNS Neuroscience and Therapeutics   28 ( 6 )   922 - 931   2022年3月   ISSN:17555930

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CNS Neuroscience and Therapeutics  

    AIMS: The molecular genetic mechanisms underlying postoperative nausea and vomiting (PONV) in the brain have not been fully elucidated. This study aimed to determine the changes in whole transcriptome in the nucleus of the solitary tract (NTS) in an animal model of PONV, to screen a drug candidate and to elucidate the molecular genetic mechanisms of PONV development. METHODS: Twenty-one female musk shrews were assigned into three groups: the Surgery group (shrew PONV model, n = 9), the Sham group (n = 6), and the Naïve group (n = 6). In behavioral studies, the main outcome was the number of emetic episodes. In genetic experiments, changes in the transcriptome in the NTS were measured. In a separate study, 12 shrews were used to verify the candidate mechanism underlying PONV. RESULTS: A median of six emetic episodes occurred in both the Sham and Surgery groups. Whole-transcriptome analysis indicated the inhibition of the GABAB receptor-mediated signaling pathway in the PONV model. Baclofen (GABAB receptor agonist) administration eliminated emetic behaviors in the shrew PONV model. CONCLUSIONS: Our findings suggest that the GABAB receptor-mediated signaling pathway is involved in emesis and that baclofen may be a novel therapeutic or prophylactic agent for PONV.

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  • A single-nucleotide-polymorphism in the 5′-flanking region of MSX1 gene as a predictive marker candidate for platinum-based therapy of esophageal carcinoma 査読 国際誌

    Mori T., Ueno K., Tokunaga K., Kawai Y., Matsuda K., Nishida N., Komine K., Saito S., Nagasaki M.

    Therapeutic Advances in Medical Oncology   14   175883592210805 - 175883592210805   2022年2月   ISSN:1758-8359

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Therapeutic Advances in Medical Oncology  

    <jats:sec><jats:title>Background:</jats:title><jats:p> Platinum derivatives are important treatment options for patients with esophageal carcinoma (EC), and a predictive marker for platinum-based therapy is needed for precision medicine. </jats:p></jats:sec><jats:sec><jats:title>Patients and methods:</jats:title><jats:p> This study contained two cohorts consisting of EC patients treated using platinum-based chemoradiation therapy (CRT) as the first-line and another external cohort of nationwide clinicogenomic data from the BioBank Japan (BBJ). </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> Genome-wide association study (GWAS) of therapeutic outcomes, refractory disease or not, following platinum-based CRT as first-line in 94 patients in the first cohort suggested the association of 89 SNPs using p < 0.0001. The top 10 SNPs selected from each chromosomal region by odds ratio were evaluated for progression-free survival (PFS) and overall survival (OS) hazard ratios in the first cohort, resulting in four candidates ( p < 0.0025). The four selected candidates were re-evaluated in another cohort of 24 EC patients, which included patients prospectively enrolled in this study to fulfill the sample size statistically suggested by the results of the first cohort, and of the four, only rs3815544 was replicated ( p < 0.0125). Furthermore, this candidate genotype of rs3815544 proceeded to the re-evaluation study in an external cohort consisting of EC patients treated with platinum derivatives and/or by radiation therapy as the first-line treatment in BBJ, which confirmed that the alternative allele (G) of rs3815544 was statistically associated with non-response (SD or PD) to platinum-based therapy in EC patients (odds ratio = 1.801, p = 0.048). The methylation QTL database as well as online clinicogenomic databases suggested that the region including rs3815544 may regulate MSX1 expression through CpG methylation, and this down-regulation was statistically associated with poor prognosis after platinum-based therapies for EC. </jats:p></jats:sec><jats:sec><jats:title>Conclusion:</jats:title><jats:p> rs3815544 is a novel candidate predictive marker for platinum-based EC therapy. </jats:p></jats:sec>

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  • Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease 査読

    Suzuki K., Kakuta Y., Naito T., Takagawa T., Hanai H., Araki H., Sasaki Y., Sakuraba H., Sasaki M., Hisamatsu T., Motoya S., Matsumoto T., Onodera M., Ishiguro Y., Nakase H., Andoh A., Hiraoka S., Shinozaki M., Fujii T., Katsurada T., Kobayashi T., Fujiya M., Otsuka T., Oshima N., Suzuki Y., Sato Y., Hokari R., Noguchi M., Ohta Y., Matsuura M., Kawai Y., Tokunaga K., Nagasaki M., Kudo H., Minegishi N., Okamoto D., Shimoyama Y., Moroi R., Kuroha M., Shiga H., Li D., McGovern D.P.B., Kinouchi Y., Masamune A., Ikeya K., Nishida A., Nakagawa S., Miura M., Toyonaga T., Onodera K., Takahara M., Yanai S., Ishihara S., Nagahori M., Matsuoka K., Arai K., Mizuno S., Naganuma M., Nakamura S., Ishikawa T., Nakajima H., Terasaki H., Saito R., Amemiya I., Ohyama H., Korekawa K., Iwaki H., Takahashi S., Makuuchi M., Inomata Y., Shimoda F., Takahashi T., Yano K., Abe I., Handa T., Masu Y., Hishinuma K., Kanazawa Y., Kimura T., Negoro K., Kato M.

    Inflammatory Bowel Diseases   28 ( 1 )   21 - 31   2022年1月   ISSN:10780998

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    出版者・発行元:Inflammatory Bowel Diseases  

    Background: Some patients with inflammatory bowel disease (IBD) who were under mesalamine treatment develop adverse reactions called "mesalamine allergy,"which includes high fever and worsening diarrhea. Currently, there is no method to predict mesalamine allergy. Pharmacogenomic approaches may help identify these patients. Here we analyzed the genetic background of mesalamine intolerance in the first genome-wide association study of Japanese patients with IBD. Methods: Two independent pharmacogenetic IBD cohorts were analyzed: the MENDEL (n = 1523; as a discovery set) and the Tohoku (n = 788; as a replication set) cohorts. Genome-wide association studies were performed in each population, followed by a meta-analysis. In addition, we constructed a polygenic risk score model and combined genetic and clinical factors to model mesalamine intolerance. Results: In the combined cohort, mesalamine-induced fever and/or diarrhea was significantly more frequent in ulcerative colitis vs Crohn's disease. The genome-wide association studies and meta-analysis identified one significant association between rs144384547 (upstream of RGS17) and mesalamine-induced fever and diarrhea (P = 7.21e-09; odds ratio = 11.2). The estimated heritability of mesalamine allergy was 25.4%, suggesting a significant correlation with the genetic background. Furthermore, a polygenic risk score model was built to predict mesalamine allergy (P = 2.95e-2). The combined genetic/clinical prediction model yielded a higher area under the curve than did the polygenic risk score or clinical model alone (area under the curve, 0.89; sensitivity, 71.4%; specificity, 90.8%). Conclusions: Mesalamine allergy was more common in ulcerative colitis than in Crohn's disease. We identified a novel genetic association with and developed a combined clinical/genetic model for this adverse event.

    DOI: 10.1093/ibd/izab004

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  • rs9459874 and rs1012656 in CCR6/FGFR1OP confer susceptibility to primary biliary cholangitis 査読 国際誌

    Hitomi Y., Aiba Y., Ueno K., Nishida N., Kawai Y., Kawashima M., Yasunami M., Gervais O., Ito M., Cordell H.J., Mells G.F., Nagasaki M., Tokunaga K., Tsuiji M., Nakamura M.

    Journal of Autoimmunity   126   102775 - 102775   2022年1月   ISSN:08968411

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Autoimmunity  

    Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease that appears to be strongly influenced by genetic factors. Recently, an international meta-analysis of genome-wide association studies (GWAS) identified CC-Motif Chemokine Receptor-6 (CCR6) and FGFR1 Oncogene-Partner (FGFR1OP) as PBC-susceptibility genes. However, the lead single nucleotide polymorphisms (SNPs) of CCR6/FGFR1OP showed low linkage disequilibrium with each other in East Asian and European populations. Additionally, the primary functional variants and the molecular mechanisms responsible for PBC-susceptibility remain unclear. Here, among the PBC-susceptibility SNPs identified by high-density association mapping in our previous meta-GWAS (Patients: n = 10,516; healthy controls: n = 20,772) within the CCR6/FGFR1OP locus, rs9459874 and rs1012656 were identified as primary functional variants. These functional variants accounted for the effects of GWAS-identified lead SNPs in CCR6/FGFR1OP. Additionally, the roles of rs9459874 and rs1012656 in regulating FGFR1OP transcription and CCR6 translation, respectively, were supported by expression quantitative trait loci (eQTL) analysis and gene editing technology using the CRISPR/Cas9 system. Immunohistochemistry showed higher expression of CCR6 protein in the livers of patients with PBC than in those of a non-diseased control. In conclusion, we identified primary functional variants in CCR6/FGFR1OP and revealed the molecular mechanisms by which these variants confer PBC-susceptibility in an eQTL-dependent or -independent manner. The approach in this study is applicable for the elucidation of the pathogenesis of other autoimmune disorders in which CCR6/FGFR1OP is known as a susceptibility locus, as well as PBC.

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  • Mapping of susceptible variants for cold medicine-related Stevens–Johnson syndrome by whole-genome resequencing 査読 国際誌

    Yosuke Kawai, Yuki Hitomi, Mayumi Ueta, Seik-Soon Khor, Ken Nakatani, Chie Sotozono, Shigeru Kinoshita, Masao Nagasaki, Katsushi Tokunaga

    npj Genomic Medicine   6 ( 1 )   9 - 9   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Stevens-Johnson syndrome (SJS) and its severe condition with extensive skin detachment and a poor prognosis, toxic epidermal necrolysis (TEN), are immunologically mediated severe cutaneous reactions of the skin and mucous membranes such as the ocular surface. Genetic variations on the HLA-A and other autosomal genes have been identified as risk factors for cold medicine-related SJS/TEN with severe ocular complications (CM-SJS/TEN with SOC). Using a whole-genome sequencing (WGS) approach, we explored other susceptible variants of CM-SJS/TEN with SOC, especially among rare variants and structural variants (SVs). WGS was performed on samples from 133 patients with CM-SJS/TEN with SOC and 418 healthy controls to obtain single nucleotide polymorphisms (SNPs) and SVs. Genome-wide association tests were performed with these variants. Our genome-wide association test reproduced the associations of the common variants of HLA-A and loci on chromosome 16q12.1. We also identified novel associations of SVs on these loci and an aggregation of rare coding variants on the TPRM8 gene. In silico gene expression analysis on the HLA-A locus revealed that the SNP (rs12202296), which was significantly associated with susceptibility to CM-SJS/TEN with SOC, was correlated to an increase in HLA-A expression levels in the whole blood (P = 2.9 × 10-17), from the GTEx database. The majority of variants that were significantly associated with CM-SJS/TEN with SOC were found in non-coding regions, indicating the regulatory role of genetic variations in the pathogenesis of CM-SJS/TEN with SOC.

    DOI: 10.1038/s41525-021-00171-2

  • Crohn's Disease and Early Exposure to Thiopurines are Independent Risk Factors for Mosaic Chromosomal Alterations in Patients with Inflammatory Bowel Diseases 査読 国際誌

    Kakuta, Y; Iwaki, H; Umeno, J; Kawai, Y; Kawahara, M; Takagawa, T; Shimoyama, Y; Naito, T; Moroi, R; Kuroha, M; Shiga, H; Watanabe, K; Nakamura, S; Nakase, H; Sasaki, M; Hanai, H; Fuyuno, Y; Hirano, A; Matsumoto, T; Kudo, H; Minegishi, N; Nakamura, M; Hisamatsu, T; Andoh, A; Nagasaki, M; Tokunaga, K; Kinouchi, Y; Masamune, A

    JOURNAL OF CROHNS & COLITIS   16 ( 4 )   643 - 655   2021年11月   ISSN:1873-9946 eISSN:1876-4479

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Crohn's and Colitis  

    BACKGROUND AND AIMS: Mosaic chromosomal alterations (mCAs) increase the risk for hematopoietic malignancies and may be risk factors for several other diseases. Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are associated with mCAs, and patients may be at risk for hematopoietic malignancy development and/or modification of IBD phenotypes. In the present study, we screened patients with IBD for the presence of mCAs and explored the possible pathophysiological and genetic risk factors for mCAs. METHODS: We analyzed mCAs in peripheral blood from 3,339 patients with IBD and investigated the clinical and genetic risk factors for mCAs. RESULTS: CD and exposure to thiopurines before the age of 20 years were identified as novel independent risk factors for mCAs (odds ratio = 2.15 and 5.68, P = 1.17e-2 and 1.60e-3, respectively). In contrast, there were no significant associations of disease duration, anti-tumor necrosis factor alpha antibodies, or other clinical factors with mCAs. Gene ontology enrichment analysis revealed that genes specifically located in the mCAs in patients with CD were significantly associated with factors related to mucosal immune responses. A genome-wide association study revealed that ERBIN, CD96, and AC068672.2 were significantly associated with mCAs in patients with CD (P = 1.56e-8, 1.65e-8, and 4.92e-8, respectively). CONCLUSION: The difference in mCAs between patients with CD and UC supports the higher incidence of hematopoietic malignancies in CD. Caution should be exercised when using thiopurines in young patients with IBD, particularly CD, in light of possible chromosomal alterations.

    DOI: 10.1093/ecco-jcc/jjab199

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    PubMed

  • Machine learning approaches to predict gestational age in normal and complicated pregnancies via urinary metabolomics analysis. 査読 国際誌

    Takafumi Yamauchi, Daisuke Ochi, Naomi Matsukawa, Daisuke Saigusa, Mami Ishikuro, Taku Obara, Yoshiki Tsunemoto, Satsuki Kumatani, Riu Yamashita, Osamu Tanabe, Naoko Minegishi, Seizo Koshiba, Hirohito Metoki, Shinichi Kuriyama, Nobuo Yaegashi, Masayuki Yamamoto, Masao Nagasaki, Satoshi Hiyama, Junichi Sugawara

    Scientific reports   11 ( 1 )   17777 - 17777   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The elucidation of dynamic metabolomic changes during gestation is particularly important for the development of methods to evaluate pregnancy status or achieve earlier detection of pregnancy-related complications. Some studies have constructed models to evaluate pregnancy status and predict gestational age using omics data from blood biospecimens; however, less invasive methods are desired. Here we propose a model to predict gestational age, using urinary metabolite information. In our prospective cohort study, we collected 2741 urine samples from 187 healthy pregnant women, 23 patients with hypertensive disorders of pregnancy, and 14 patients with spontaneous preterm birth. Using gas chromatography-tandem mass spectrometry, we identified 184 urinary metabolites that showed dynamic systematic changes in healthy pregnant women according to gestational age. A model to predict gestational age during normal pregnancy progression was constructed; the correlation coefficient between actual and predicted weeks of gestation was 0.86. The predicted gestational ages of cases with hypertensive disorders of pregnancy exhibited significant progression, compared with actual gestational ages. This is the first study to predict gestational age in normal and complicated pregnancies by using urinary metabolite information. Minimally invasive urinary metabolomics might facilitate changes in the prediction of gestational age in various clinical settings.

    DOI: 10.1038/s41598-021-97342-z

  • まれな変異に重点を置いた尿酸値の遺伝率の研究

    三澤 計治, 三島 英換, 長谷川 嵩矩, 大内 基司, 小島 要, 河合 洋介, 松尾 雅文, 安西 尚彦, 長崎 正朗

    痛風と尿酸・核酸   45 ( 1 )   23 - 30   2021年7月

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    記述言語:日本語  

    痛風は,尿酸が原因で起こる関節炎であり,罹患者も多い.先行研究では血清尿酸値の遺伝率は30~70%と推定されている.遺伝子ベース検定を用いた最近の研究では,まれな変異の有無がヒト集団中の血清尿酸値分散に大きく寄与していることが示唆されている.遺伝子ベース検定は,1つの遺伝子に含まれる複数の遺伝子変異の影響を1回の検定で考慮するものである.本論文では,数値計算を用い,遺伝子ベース検定のサンプルサイズと検出力の関係を解析した.仮想的なヒト集団を,まれな変異を持つ人々と持たない人々の二つの群に分けた.この二群間での尿酸値の平均値の差は,先行研究によるURAT1変異の有無によって生じる差と同じ値を使った.また,各個人の尿酸値は,その個人が属する各群の平均値を期待値とする正規分布に従うと仮定した.等分散性を仮定しないWelchのt検定を行い,検出力を計算した.今回の数値計算から,まれな変異は,一つのSNPだけを用いている場合,1万人から数万人ほどの大きさのサンプルが必要であることがわかった.複数のSNPをまとめた検定を行うことで,検出力が上がり,数百から数千人規模の研究でも検出できることが示された.この研究は,今まで主に研究対象となってきた「ありふれた疾患,ありふれた変異」に加え,遺伝子ベース検定による,「ありふれた疾患,まれな変異」の研究の可能性を示した.(著者抄録)

  • X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis. 査読 国際誌

    Rosanna Asselta, Elvezia M Paraboschi, Alessio Gerussi, Heather J Cordell, George F Mells, Richard N Sandford, David E Jones, Minoru Nakamura, Kazuko Ueno, Yuki Hitomi, Minae Kawashima, Nao Nishida, Katsushi Tokunaga, Masao Nagasaki, Atsushi Tanaka, Ruqi Tang, Zhiqiang Li, Yongyong Shi, Xiangdong Liu, Ma Xiong, Gideon Hirschfield, Katherine A Siminovitch, Marco Carbone, Giulia Cardamone, Stefano Duga, M Eric Gershwin, Michael F Seldin, Pietro Invernizzi

    Gastroenterology   160 ( 7 )   2483 - 2495   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND & AIMS: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. METHODS: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). RESULTS: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). CONCLUSIONS: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

    DOI: 10.1053/j.gastro.2021.02.061

  • An international genome-wide meta-analysis of primary biliary cholangitis: novel risk loci and candidate drugs 査読 国際誌

    Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byan, Younghun Han, Richard N. S, ford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Katherine A. Siminovitch, Gideon M. Hirschfield, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Ruqi Tang, Xiong Ma, Zhiqiang Li, Yongyong Shi, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, MariaConsiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Croc{`{e } }, Andrea Crosignani, Daphne D'Amato, Francesca Donato, Gianfranco Elia, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O'Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo K, a, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, H. Egawa, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton VJ. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Rol, Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris DJ. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom JW. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch{ extquotesingle}ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya M, al, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, Charles Millson, Brian D. Juran, Elizabeth J. Atkinson, Angela Cheung, Mariza de Andrade, Konstantinos N. Lazaridis, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Aris Baras, Julie Horowitz, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alex, er Lopez, John D. Overton, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Lel, Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Jeffrey G. Reid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul

    Journal of Hepatology   75 ( 3 )   572 - 581   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUNDS & AIMS: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. METHODS: We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. RESULTS: We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. CONCLUSIONS: This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. LAY SUMMARY: Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these 'candidate genes' to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC.

    DOI: 10.1016/j.jhep.2021.04.055

  • Regional heritability mapping identifies several novel loci (STAT4, ULK4, and KCNH5) for primary biliary cholangitis in the Japanese population 査読 国際誌

    Olivier Gervais, Kazuko Ueno, Yosuke Kawai, Yuki Hitomi, Yoshihiro Aiba, Mayumi Ueta, Minoru Nakamura, Katsushi Tokunaga, Masao Nagasaki

    European Journal of Human Genetics   29 ( 8 )   1282 - 1291   2021年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    While the advent of GWAS more than a decade ago has ushered in remarkable advances in our understanding of complex traits, the limitations of single-SNP analysis have also led to the development of several other approaches. Simulation studies have shown that the regional heritability mapping (RHM) method, which makes use of multiple adjacent SNPs jointly to estimate the genetic effect of a given region of the genome, generally has higher detection power than single-SNP GWAS. However, thus far its use has been mostly limited to agricultural settings, and its potential for the discovery of new genes in human diseases is yet to be fully exploited. In this study, by applying the RHM method to primary biliary cholangitis (PBC) in the Japanese population, we identified three novel loci (STAT4, ULK4, and KCNH5) at the genome-wide significance level, two of which (ULK4 and KCNH5) have not been found associated with PBC in any population previously. Notably, these genes could not be detected by using conventional single-SNP GWAS, highlighting the potential of the RHM method for the detection of new susceptibility loci in human diseases. These findings thereby provide strong empirical evidence that RHM is an effective and practical complementary approach to GWAS in this context. Also, liver tissue mRNA microarray analysis revealed higher gene expression levels in ULK4 in PBC patients (P < 0.01). Lastly, we estimated the common SNP heritability of PBC in the Japanese population (0.210 ± 0.026).

    DOI: 10.1038/s41431-021-00854-5

  • High-speed parameter search of dynamic biological pathways from time-course transcriptomic profiles using high-level Petri net 査読

    Chen Li, Jiale Qin, Keisuke Kuroyanagi, Lu Lu, Masao Nagasaki, Miyano Satoru

    Biosystems   201   104332 - 104332   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.biosystems.2020.104332

  • rs1944919 on chromosome 11q23.1 and its effector genes COLCA1/COLCA2 confer susceptibility to primary biliary cholangitis. 査読 国際誌

    Yuki Hitomi, Yoshihiro Aiba, Yosuke Kawai, Kaname Kojima, Kazuko Ueno, Nao Nishida, Minae Kawashima, Olivier Gervais, Seik-Soon Khor, Masao Nagasaki, Katsushi Tokunaga, Minoru Nakamura, Makoto Tsuiji

    Scientific reports   11 ( 1 )   4557 - 4557   2021年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Primary biliary cholangitis (PBC) is a chronic, progressive cholestatic liver disease in which intrahepatic bile ducts are destroyed by an autoimmune reaction. Our previous genome-wide association study (GWAS) identified chromosome 11q23.1 as a susceptibility gene locus for PBC in the Japanese population. Here, high-density association mapping based on single nucleotide polymorphism (SNP) imputation and in silico/in vitro functional analyses identified rs1944919 as the primary functional variant. Expression-quantitative trait loci analyses showed that the PBC susceptibility allele of rs1944919 was significantly associated with increased COLCA1/COLCA2 expression levels. Additionally, the effects of rs1944919 on COLCA1/COLCA2 expression levels were confirmed using genotype knock-in versions of cell lines constructed using the CRISPR/Cas9 system and differed between rs1944919-G/G clones and -T/T clones. To our knowledge, this is the first study to demonstrate the contribution of COLCA1/COLCA2 to PBC susceptibility.

    DOI: 10.1038/s41598-021-84042-x

  • Practical guide for managing large-scale human genome data in research 査読

    Tomoya Tanjo, Yosuke Kawai, Katsushi Tokunaga, Osamu Ogasawara, Masao Nagasaki

    Journal of Human Genetics   66 ( 1 )   39 - 52   2021年1月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    <title>Abstract</title>Studies in human genetics deal with a plethora of human genome sequencing data that are generated from specimens as well as available on public domains. With the development of various bioinformatics applications, maintaining the productivity of research, managing human genome data, and analyzing downstream data is essential. This review aims to guide struggling researchers to process and analyze these large-scale genomic data to extract relevant information for improved downstream analyses. Here, we discuss worldwide human genome projects that could be integrated into any data for improved analysis. Obtaining human whole-genome sequencing data from both data stores and processes is costly; therefore, we focus on the development of data format and software that manipulate whole-genome sequencing. Once the sequencing is complete and its format and data processing tools are selected, a computational platform is required. For the platform, we describe a multi-cloud strategy that balances between cost, performance, and customizability. A good quality published research relies on data reproducibility to ensure quality results, reusability for applications to other datasets, as well as scalability for the future increase of datasets. To solve these, we describe several key technologies developed in computer science, including workflow engine. We also discuss the ethical guidelines inevitable for human genomic data analysis that differ from model organisms. Finally, the future ideal perspective of data processing and analysis is summarized.

    DOI: 10.1038/s10038-020-00862-1

  • A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis 査読

    Masao Nagasaki

    Communications Biology   3 ( 1 )   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    <jats:title>Abstract</jats:title>
    <jats:p>Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the <jats:italic>ACSL5</jats:italic> locus (top SNP <jats:italic>p</jats:italic> = 2.97 × 10<jats:sup>−8</jats:sup>). We validated the association with <jats:italic>ACSL5</jats:italic> in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP <jats:italic>p</jats:italic> = 1.82 × 10<jats:sup>−4</jats:sup>). In the combined meta-analysis, the intronic <jats:italic>ACSL5</jats:italic> SNP rs3736947 showed the strongest association (<jats:italic>p</jats:italic> = 7.81 × 10<jats:sup>−11</jats:sup>). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: <jats:italic>ERGIC1</jats:italic>, <jats:italic>RAPGEF5</jats:italic>, <jats:italic>FNBP1</jats:italic>, and <jats:italic>ATXN3</jats:italic>. These results advance our understanding of the genetic basis of sporadic ALS.</jats:p>

    DOI: 10.1038/s42003-020-01251-2

  • Long non-coding RNA MIR4300HG polymorphisms are associated with postoperative nausea and vomiting: a genome-wide association study 査読

    Masao Nagasaki

    Human Genomics   14 ( 1 )   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    <jats:title>Abstract</jats:title>
    <jats:sec>
    <jats:title>Background</jats:title>
    <jats:p>Genetic factors such as single-nucleotide polymorphisms (SNPs) play a key role in the development of postoperative nausea and vomiting (PONV). However, previous findings are not widely applicable to different populations because of population-specific genetic variation. We developed a Japanese-specific DNA microarray for high-throughput genotyping. The aim of the current study was to identify SNPs associated with PONV on a genome-wide scale using this microarray in a sample of Japanese surgical patients.</jats:p>
    </jats:sec>
    <jats:sec>
    <jats:title>Methods</jats:title>
    <jats:p>Associations between 659,636 SNPs and the incidence of PONV 24 h after surgery in a limited sample of 24 female patients were assessed using the microarray. After imputation of genotypes at 24,330,529 SNPs, 78 SNPs were found to be associated with the incidence of PONV. We chose 4 of the 78 SNPs to focus on by in silico functional annotation. Finally, we genotyped these 4 candidate SNPs in 255 patients using real-time PCR to verify association with the incidence of PONV.</jats:p>
    </jats:sec>
    <jats:sec>
    <jats:title>Results</jats:title>
    <jats:p>The T > C variant of rs11232965 in the long non-coding RNA MIR4300HG was significantly associated with reduced incidence of PONV among genotypes and between alleles (<jats:italic>p</jats:italic> = 0.01 and 0.007).</jats:p>
    </jats:sec>
    <jats:sec>
    <jats:title>Conclusions</jats:title>
    <jats:p>We identified a novel SNP (rs11232965) in the long non-coding RNA MIR4300HG that is associated with PONV. The rs11232965-SNP variant (T > C) is protective against the incidence of PONV.</jats:p>
    </jats:sec>
    <jats:sec>
    <jats:title>Trial registration</jats:title>
    <jats:p>This study was registered at the UMIN Clinical Trials Registry (Identifier: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000026392">UMIN000022903</jats:ext-link>, date of registration: June 27, 2016, retrospectively registered.</jats:p>
    </jats:sec>

    DOI: 10.1186/s40246-020-00282-4

  • Direct reprogramming of human umbilical vein- and peripheral blood-derived endothelial cells into hepatic progenitor cells 査読

    Hiroki Inada, Miyako Udono, Kanae Matsuda-Ito, Kenichi Horisawa, Yasuyuki Ohkawa, Shizuka Miura, Takeshi Goya, Junpei Yamamoto, Masao Nagasaki, Kazuko Ueno, Daisuke Saitou, Mikita Suyama, Yoshihiko Maehara, Wataru Kumamaru, Yoshihiro Ogawa, Sayaka Sekiya, Atsushi Suzuki

    Nature Communications   11 ( 1 )   2020年12月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    <title>Abstract</title>
    Recent advances have enabled the direct induction of human tissue-specific stem and progenitor cells from differentiated somatic cells. However, it is not known whether human hepatic progenitor cells (hHepPCs) can be generated from other cell types by direct lineage reprogramming with defined transcription factors. Here, we show that a set of three transcription factors, FOXA3, HNF1A, and HNF6, can induce human umbilical vein endothelial cells to directly acquire the properties of hHepPCs. These induced hHepPCs (hiHepPCs) propagate in long-term monolayer culture and differentiate into functional hepatocytes and cholangiocytes by forming cell aggregates and cystic epithelial spheroids, respectively, under three-dimensional culture conditions. After transplantation, hiHepPC-derived hepatocytes and cholangiocytes reconstitute damaged liver tissues and support hepatic function. The defined transcription factors also induce hiHepPCs from endothelial cells circulating in adult human peripheral blood. These expandable and bipotential hiHepPCs may be useful in the study and treatment of human liver diseases.

    DOI: 10.1038/s41467-020-19041-z

  • Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome. 査読

    Masao Nagasaki

    Science advances   6 ( 51 )   eabd7197 - eabd7197   2020年12月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase (ADH5FDH ), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, Adh5-/-Aldh2 E506K/E506K double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.

    DOI: 10.1126/sciadv.abd7197

  • Identification of the Novel Variants in Patients With Chronic Thromboembolic Pulmonary Hypertension. 査読 国際誌

    Nobuhiro Yaoita, Kimio Satoh, Taijyu Satoh, Toru Shimizu, Sakae Saito, Koichiro Sugimura, Shunsuke Tatebe, Saori Yamamoto, Tatsuo Aoki, Nobuhiro Kikuchi, Ryo Kurosawa, Satoshi Miyata, Masao Nagasaki, Jun Yasuda, Hiroaki Shimokawa

    Journal of the American Heart Association   9 ( 21 )   e015902   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background Although chronic thromboembolic pulmonary hypertension (CTEPH) and acute pulmonary embolism (APE) share some clinical manifestations, a limited proportion of patients with CTEPH have a history of APE. Moreover, in histopathologic studies, it has been revealed that pulmonary vasculature lesions similar to pulmonary arterial hypertension existed in patients with CTEPH. Thus, it remains unknown whether these 3 disorders also share genetic backgrounds. Methods and Results Whole exome screening was performed with DNA isolated from 51 unrelated patients with CTEPH of Japanese ancestry. The frequency of genetic variants associated with pulmonary arterial hypertension or APE in patients with CTEPH was compared with those in the integrative Japanese Genome Variation Database 3.5KJPN. Whole exome screening analysis showed 17 049 nonsynonymous variants in patients with CTEPH. Although we found 6 nonsynonymous variants that are associated with APE in patients with CTEPH, there was no nonsynonymous variant associated with pulmonary arterial hypertension. Patients with CTEPH with a history of APE had nonsynonymous variants of F5, which encodes factor V. In contrast, patients with CTEPH without a history of APE had a nonsynonymous variant of THBD, which encodes thrombomodulin. Moreover, thrombin-activatable fibrinolysis inhibitor, which is one of the pathogenic proteins in CTEPH, was significantly more activated in those who had the variants of THBD compared with those without it. Conclusions These results provide the first evidence that patients with CTEPH have some variants associated with APE, regardless of the presence or absence of a history of APE. Furthermore, the variants might be different between patients with CTEPH with and without a history of APE.

    DOI: 10.1161/JAHA.120.015902

  • Genome‐Wide Association Study of Lean Nonalcoholic Fatty Liver Disease Suggests Human Leukocyte Antigen as a Novel Candidate Locus 査読 国際誌

    Masao Nagasaki

    Hepatology Communications   4 ( 8 )   1124 - 1135   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Nonalcoholic fatty liver disease (NAFLD) is supposed to manifest its metabolic phenotype in the liver, but it is common to have lean individuals diagnosed with NAFLD, known as lean NAFLD. We conducted a two-stage analysis to identify NAFLD-associated loci in Japanese patients. In stage I, 275 metabolically healthy normal-weight patients with NAFLD were compared with 1,411 non-NAFLD controls adjusted for age, sex, and alcohol consumption by a genome-wide association study (GWAS). In stage II, human leukocyte antigen (HLA) in chromosome 6 (chr6) (P = 6.73E-08), microRNA (MIR) MIR548F3 in chr7 (P = 4.25E-07), myosin light chain 2 (MYL2) in chr12 (P = 4.39E-07), and glycoprotein precursor (GPC)6 in chr13 (P = 5.43E-07), as suggested by the GWAS, were assessed by single nucleotide polymorphism (SNP) association analysis of whole NAFLD against non-NAFLD in 9,726 members of the general population. A minor allele of the secondary lead SNP in chr6, rs2076529, was significantly associated (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.11-1.28; P = 2.10E-06) and the lead SNP in chr7 was weakly associated (OR 1.15; 95% CI, 1.04-1.27; P = 6.19E-03) with increased NAFLD risk. Imputation-based typing of HLA showed a significant difference in the distribution of HLA-B, HLA-DR-beta chain 1 (DRB1), and HLA-DQ-beta chain 1 (DQB1) alleles in lean NAFLD GWAS. Next-generation sequence-based typing of HLA in 5,649 members of the general population replicated the significant difference of HLA-B allele distribution and the significant increase of the HLA-B*54:01 allele in whole NAFLD. Fecal metagenomic analysis of 3,420 members of the general population showed significant dissimilarity in beta-diversity analysis of rs2076529 and HLA-B*54:01 allele carriers from noncarriers. Veillonellaceae was increased but Verrucomicrobia was decreased in rs2076529 minor allele and HLA-B*54:01 allele carriers as in NAFLD. Conclusion: HLA was identified as a novel locus associated with NAFLD susceptibility, which might be affected by the alteration of gut microbiota.

    DOI: 10.1002/hep4.1529

  • The Dynamics of Transcriptional Activation by Hepatic Reprogramming Factors 査読 国際誌

    Kenichi Horisawa, Miyako Udono, Kazuko Ueno, Yasuyuki Ohkawa, Masao Nagasaki, Sayaka Sekiya, Atsushi Suzuki

    Molecular Cell   79 ( 4 )   660 - 676.e8   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Specific combinations of two transcription factors (Hnf4α plus Foxa1, Foxa2, or Foxa3) can induce direct conversion of mouse fibroblasts into hepatocyte-like cells. However, the molecular mechanisms underlying hepatic reprogramming are largely unknown. Here, we show that the Foxa protein family members and Hnf4α sequentially and cooperatively bind to chromatin to activate liver-specific gene expression. Although all Foxa proteins bind to and open regions of closed chromatin as pioneer factors, Foxa3 has the unique potential of transferring from the distal to proximal regions of the transcription start site of target genes, binding RNA polymerase II, and co-traversing target genes. These distinctive characteristics of Foxa3 are essential for inducing the hepatic fate in fibroblasts. Similar functional coupling of transcription factors to RNA polymerase II may occur in other contexts whereby transcriptional activation can induce cell differentiation.

    DOI: 10.1016/j.molcel.2020.07.012

  • 尿酸値の失われた遺伝率は、レアバリアントがかなりの部分を説明する

    三澤 計治, 長谷川 嵩矩, 三島 英換, Jutabha Promsuk, 大内 基司, 小島 要, 河合 洋介, 長崎 正朗, 安西 尚彦

    痛風と尿酸・核酸   44 ( 1 )   86 - 86   2020年7月

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    記述言語:日本語  

  • Genomic Heritabilities and Correlations of 17 Traits Related to Obesity and Associated Conditions in the Japanese Population 査読 国際誌

    Olivier Gervais, 植野 和子, 河合 洋介, 人見 祐基, 三澤 計治, 寺口 俊介, Yen-Yen Wang, 徳永 勝士, 長﨑 正朗

    G3: Genes, Genomics, Genetics   10 ( 7 )   2221 - 2228   2020年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Genomic Heritabilities and Correlations of 17 Traits Related to Obesity and Associated Conditions in the Japanese Population
    Over the past few decades, obesity has become a public health issue of global concern. Even though disparities exist between human populations, e.g., the higher liver fat content of the Japanese despite a lower body mass index (BMI), studies on the genetics of obesity still largely focus on populations of European descent, leading to a dearth of genetic data on non-European populations. In this context, this study aimed to establish a broad picture of the genetic attributes of the Japanese population, by examining a representative sample of 18,889 individuals participating in the Tohoku Medical Megabank Project cohort. We applied linear mixed model methods to 17 traits related to obesity and associated diseases to estimate the heritabilities explained by common genetic variants and the genetic correlations between each pair of traits. These analyses allowed us to quantify the SNP heritability of health indicators such as BMI (0.248 ± 0.032) and HDL cholesterol (0.324 ± 0.031), and to provide one of the few estimates of the SNP heritability of cystatin C in unrelated individuals (0.260 ± 0.025). We discuss potential differences between the Japanese and people of European ancestry with respect to the genetic correlations between urinary biomarkers and adiposity traits, for which large estimates were obtained. For instance, the genetic correlations between urine potassium level and the values for weight, BMI, waist circumference, and waist-to-height ratio ranged from 0.290 to 0.559, much higher than the corresponding estimates in the UK Biobank.

    DOI: 10.1534/g3.120.401242

  • An Integrated Genomic and Transcriptomic Analysis Reveals Candidates of Susceptibility Genes for Crohn's Disease in Japanese Populations. 査読 国際誌

    Yoichi Kakuta, Ryo Ichikawa, Yuta Fuyuno, Atsushi Hirano, Junji Umeno, Takehiro Torisu, Kazuhiro Watanabe, Akihiro Asakura, Takeru Nakano, Yasuhiro Izumiyama, Daisuke Okamoto, Takeo Naito, Rintaro Moroi, Masatake Kuroha, Yoshitake Kanazawa, Tomoya Kimura, Hisashi Shiga, Takeshi Naito, Motohiro Esaki, Yosuke Kawai, Katsushi Tokunaga, Minoru Nakamura, Takayuki Matsumoto, Masao Nagasaki, Yoshitaka Kinouchi, Michiaki Unno, Atsushi Masamune

    Scientific reports   10 ( 1 )   10236 - 10236   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Expression quantitative trait locus (eQTL) analyses have enabled us to predict the function of disease susceptibility SNPs. However, eQTL for the effector memory T cells (TEM) located in the lamina propria mononuclear cells (LPMCs), which play an important role in Crohn's disease (CD), are not yet available. Thus, we conducted RNA sequencing and eQTL analyses of TEM cells located in the LPMCs from IBD patients (n = 20). Genome-wide association study (GWAS) was performed using genotyping data of 713 Japanese CD patients and 2,063 controls. We compared the results of GWAS and eQTL of TEM, and also performed a transcriptome-wide association study using eQTL from Genotype Tissue Expression project. By eQTL analyses of TEM, correlations of possible candidates were confirmed in 22,632 pairs and 2,463 genes. Among these candidates, 19 SNPs which showed significant correlation with tenascin-XA (TNXA) expression were significantly associated with CD in GWAS. By TWAS, TNFSF15 (FDR = 1.35e-13) in whole blood, ERV3-1 (FDR = 2.18e-2) in lymphocytes, and ZNF713 (FDR = 3.04e-2) in the sigmoid colon was significantly associated with CD. By conducting integration analyses using GWAS and eQTL data, we confirmed multiple gene transcripts are involved in the development of CD.

    DOI: 10.1038/s41598-020-66951-5

  • Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome. 査読 国際誌

    Tomoko Kaneyasu, Seiichi Mori, Hideko Yamauchi, Shozo Ohsumi, Shinji Ohno, Daisuke Aoki, Shinichi Baba, Junko Kawano, Yoshio Miki, Naomichi Matsumoto, Masao Nagasaki, Reiko Yoshida, Sadako Akashi-Tanaka, Takuji Iwase, Dai Kitagawa, Kenta Masuda, Akira Hirasawa, Masami Arai, Junko Takei, Yoshimi Ide, Osamu Gotoh, Noriko Yaguchi, Mitsuyo Nishi, Keika Kaneko, Yumi Matsuyama, Megumi Okawa, Misato Suzuki, Aya Nezu, Shiro Yokoyama, Sayuri Amino, Mayuko Inuzuka, Tetsuo Noda, Seigo Nakamura

    NPJ breast cancer   6   25 - 25   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Panel sequencing of susceptibility genes for hereditary breast and ovarian cancer (HBOC) syndrome has uncovered numerous germline variants; however, their pathogenic relevance and ethnic diversity remain unclear. Here, we examined the prevalence of germline variants among 568 Japanese patients with BRCA1/2-wildtype HBOC syndrome and a strong family history. Pathogenic or likely pathogenic variants were identified on 12 causal genes for 37 cases (6.5%), with recurrence for 4 SNVs/indels and 1 CNV. Comparisons with non-cancer east-Asian populations and European familial breast cancer cohorts revealed significant enrichment of PALB2, BARD1, and BLM mutations. Younger onset was associated with but not predictive of these mutations. Significant somatic loss-of-function alterations were confirmed on the wildtype alleles of genes with germline mutations, including PALB2 additional somatic truncations. This study highlights Japanese-associated germline mutations among patients with BRCA1/2 wildtype HBOC syndrome and a strong family history, and provides evidence for the medical care of this high-risk population.

    DOI: 10.1038/s41523-020-0163-1

  • Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome 査読 国際誌

    Masao Nagasaki

    Kidney International   98 ( 5 )   1308 - 1322   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (Pmeta=6.71E-28, OR=1.88) and TNFSF15 (Pmeta=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).

    DOI: 10.1016/j.kint.2020.05.029

  • Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis. 査読 国際誌

    Kazuko Ueno, Yoshihiro Aiba, Yuki Hitomi, Shinji Shimoda, Hitomi Nakamura, Olivier Gervais, Yosuke Kawai, Minae Kawashima, Nao Nishida, Seik-Soon Kohn, Kaname Kojima, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ohta, Takuya Komura, Satoru Tsuruta, Kazuhiko Yamauchi, Tatsuro Kobata, Amane Kitasato, Tamotsu Kuroki, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Kiyoshi Migita, Hiromasa Ohira, Atsushi Tanaka, Hajime Takikawa, Masao Nagasaki, Katsushi Tokunaga, Minoru Nakamura

    Hepatology communications   4 ( 5 )   724 - 738   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Genome-wide association studies (GWASs) in European and East Asian populations have identified more than 40 disease-susceptibility genes in primary biliary cholangitis (PBC). The aim of this study is to computationally identify disease pathways, upstream regulators, and therapeutic targets in PBC through integrated GWAS and messenger RNA (mRNA) microarray analysis. Disease pathways and upstream regulators were analyzed with ingenuity pathway analysis in data set 1 for GWASs (1,920 patients with PBC and 1,770 controls), which included 261 annotated genes derived from 6,760 single-nucleotide polymorphisms (P < 0.00001), and data set 2 for mRNA microarray analysis of liver biopsy specimens (36 patients with PBC and 5 normal controls), which included 1,574 genes with fold change >2 versus controls (P < 0.05). Hierarchical cluster analysis and categorization of cell type-specific genes were performed for data set 2. There were 27 genes, 10 pathways, and 149 upstream regulators that overlapped between data sets 1 and 2. All 10 pathways were immune-related. The most significant common upstream regulators associated with PBC disease susceptibility identified were interferon-gamma (IFNG) and CD40 ligand (CD40L). Hierarchical cluster analysis of data set 2 revealed two distinct groups of patients with PBC by disease activity. The most significant upstream regulators associated with disease activity were IFNG and CD40L. Several molecules expressed in B cells, T cells, Kupffer cells, and natural killer-like cells were identified as potential therapeutic targets in PBC with reference to a recently reported list of cell type-specific gene expression in the liver. Conclusion: Our integrated analysis using GWAS and mRNA microarray data sets predicted that IFNG and CD40L are the central upstream regulators in both disease susceptibility and activity of PBC and identified potential downstream therapeutic targets.

    DOI: 10.1002/hep4.1497

  • Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis. 査読 国際誌

    Atsushi Masamune, Hiroshi Kotani, Franziska Lena Sörgel, Jian-Min Chen, Shin Hamada, Reiko Sakaguchi, Emmanuelle Masson, Eriko Nakano, Yoichi Kakuta, Tetsuya Niihori, Ryo Funayama, Matsuyuki Shirota, Tatsuya Hirano, Tetsuya Kawamoto, Atsuki Hosokoshi, Kiyoshi Kume, Lara Unger, Maren Ewers, Helmut Laumen, Peter Bugert, Masayuki X Mori, Volodymyr Tsvilovskyy, Petra Weißgerber, Ulrich Kriebs, Claudia Fecher-Trost, Marc Freichel, Kalliope N Diakopoulos, Alexandra Berninger, Marina Lesina, Kentaro Ishii, Takao Itoi, Tsukasa Ikeura, Kazuichi Okazaki, Tom Kaune, Jonas Rosendahl, Masao Nagasaki, Yasuhito Uezono, Hana Algül, Keiko Nakayama, Yoichi Matsubara, Yoko Aoki, Claude Férec, Yasuo Mori, Heiko Witt, Tooru Shimosegawa

    Gastroenterology   158 ( 6 )   1626 - 1641   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND & AIMS: Changes in pancreatic calcium levels affect secretion and might be involved in development of chronic pancreatitis (CP). We investigated the association of CP with the transient receptor potential cation channel subfamily V member 6 gene (TRPV6), which encodes a Ca2+-selective ion channel, in an international cohort of patients and in mice. METHODS: We performed whole-exome DNA sequencing from a patient with idiopathic CP and from his parents, who did not have CP. We validated our findings by sequencing DNA from 300 patients with CP (not associated with alcohol consumption) and 1070 persons from the general population in Japan (control individuals). In replication studies, we sequenced DNA from patients with early-onset CP (20 years or younger) not associated with alcohol consumption from France (n = 470) and Germany (n = 410). We expressed TRPV6 variants in HEK293 cells and measured their activity using Ca2+ imaging assays. CP was induced by repeated injections of cerulein in TRPV6mut/mut mice. RESULTS: We identified the variants c.629C>T (p.A210V) and c.970G>A (p.D324N) in TRPV6 in the index patient. Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3-371.7; P = 2.4 × 10-8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P = 6.2 × 10-8). Variants that did not affect the function of the TRPV6 product (p.I223T and p.D324N) were overrepresented in Japanese patients vs control individuals (OR, 10.9; 95% CI, 4.5-25.9; P = 7.4 × 10-9 for p.I223T and P = .01 for p.D324N), whereas the p.L299Q was overrepresented in European patients vs control individuals (OR, 3.0; 95% CI, 1.9-4.8; P = 1.2 × 10-5). TRPV6mut/mut mice given cerulein developed more severe pancreatitis than control mice, as shown by increased levels of pancreatic enzymes, histologic alterations, and pancreatic fibrosis. CONCLUSIONS: We found that patients with early-onset CP not associated with alcohol consumption carry variants in TRPV6 that affect the function of its product, perhaps by altering Ca2+ balance in pancreatic cells. TRPV6 regulates Ca2+ homeostasis and pancreatic inflammation.

    DOI: 10.1053/j.gastro.2020.01.005

  • Longitudinal plasma amino acid profiling with maternal genomic background throughout human pregnancy 査読 国際誌

    Matsuyuki Shirota, Daisuke Saigusa, Riu Yamashita, Yasutake Kato, Mitsuyo Matsumoto, Junya Yamagishi, Noriko Ishida, Kazuki Kumada, Yuji Oe, Hisaaki Kudo, Junji Yokozawa, Yoko Kuroki, Ikuko Motoike, Fumiki Katsuoka, Masao Nagasaki, Seizo Koshiba, Keiko Nakayama, Osamu Tanabe, Jun Yasuda, Shigeo Kure, Kengo Kinoshita, Hirohito Metoki, Shinichi Kuriyama, Nobuo Yaegashi, Masayuki Yamamoto, Junichi Sugawara

    Medical Mass Spectrometry   4 ( 1 )   36 - 49   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.24508/mms.2020.06.001

  • Cohort Profile: Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study): rationale, progress and perspective. 査読 国際誌

    Shinichi Kuriyama, Hirohito Metoki, Masahiro Kikuya, Taku Obara, Mami Ishikuro, Chizuru Yamanaka, Masato Nagai, Hiroko Matsubara, Tomoko Kobayashi, Junichi Sugawara, Gen Tamiya, Atsushi Hozawa, Naoki Nakaya, Naho Tsuchiya, Tomohiro Nakamura, Akira Narita, Mana Kogure, Takumi Hirata, Ichiro Tsuji, Fuji Nagami, Nobuo Fuse, Tomohiko Arai, Yoshio Kawaguchi, Shinichi Higuchi, Masaki Sakaida, Yoichi Suzuki, Noriko Osumi, Keiko Nakayama, Kiyoshi Ito, Shinichi Egawa, Koichi Chida, Eiichi Kodama, Hideyasu Kiyomoto, Tadashi Ishii, Akito Tsuboi, Hiroaki Tomita, Yasuyuki Taki, Hiroshi Kawame, Kichiya Suzuki, Naoto Ishii, Soichi Ogishima, Satoshi Mizuno, Takako Takai-Igarashi, Naoko Minegishi, Jun Yasuda, Kazuhiko Igarashi, Ritsuko Shimizu, Masao Nagasaki, Osamu Tanabe, Seizo Koshiba, Hiroaki Hashizume, Hozumi Motohashi, Teiji Tominaga, Sadayoshi Ito, Kozo Tanno, Kiyomi Sakata, Atsushi Shimizu, Jiro Hitomi, Makoto Sasaki, Kengo Kinoshita, Hiroshi Tanaka, Tadao Kobayashi, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto

    International journal of epidemiology   49 ( 1 )   18 - 19   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1093/ije/dyz169

  • Genetic Analysis of Ulcerative Colitis in Japanese Individuals Using Population-specific SNP Array. 査読 国際誌

    Daisuke Okamoto, Yosuke Kawai, Yoichi Kakuta, Takeo Naito, Takehiro Torisu, Atsushi Hirano, Junji Umeno, Yuta Fuyuno, Dalin Li, Takeru Nakano, Yasuhiro Izumiyama, Ryo Ichikawa, Keiichiro Hiramoto, Rintaro Moroi, Masatake Kuroha, Yoshitake Kanazawa, Hisashi Shiga, Katsushi Tokunaga, Minoru Nakamura, Motohiro Esaki, Takayuki Matsumoto, Dermot P B McGovern, Masao Nagasaki, Yoshitaka Kinouchi, Atsushi Masamune

    Inflammatory bowel diseases   26 ( 8 )   1177 - 1187   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: To clarify the genetic background of ulcerative colitis (UC) in the Japanese population, we conducted a genome-wide association study (GWAS) using a population-specific single nucleotide polymorphism (SNP) array. METHODS: We performed a GWAS and replication study including 1676 UC patients and 2381 healthy controls. The probability of colectomy was compared between genotypes of rs117506082, the top hit SNP at HLA loci, by the Kaplan-Meier method. We studied serum expression of miR-622, a newly identified candidate gene, from 32 UC patients and 8 healthy controls by quantitative reverse-transcription polymerase chain reaction. RESULTS: In the GWAS, only the HLA loci showed genome-wide significant associations with UC (rs117506082, P = 6.69E-28). Seven nominally significant regions included 2 known loci, IL23R (rs76418789, P = 6.29E-7) and IRF8 (rs16940202, P = 1.03E-6), and 5 novel loci: MIR622 (rs9560575, P = 8.23E-7), 14q31 (rs117618617, P = 1.53E-6), KAT6B (rs12260609, P = 1.81E-6), PAX3-CCDC140-SGPP2 (rs7589797, P = 2.87E-6), and KCNA2 (rs118020656, P = 4.01E-6). Combined analysis revealed that IL23R p.G149R (rs76418789, P = 9.03E-11; odds ratio [OR], 0.51) had genome-wide significant association with UC. Patients with GG genotype of rs117506082 had a significantly lower probability of total colectomy than those with the GA+AA genotype (P = 1.72E-2). Serum expression of miR-622 in patients with inactive UC tended to be higher than in healthy controls and patients with active UC (inactive UC vs healthy controls, P = 3.03E-02; inactive UC vs active UC, P = 6.44E-02). CONCLUSIONS: IL23R p.G149R is a susceptibility locus for UC in Japanese individuals. The GG genotype of rs117506082 at HLA loci may predict a better clinical course.

    DOI: 10.1093/ibd/izaa033

  • Exploring the Novel Susceptibility Gene Variants for Primary Open-Angle Glaucoma in East Asian Cohorts: The GLAU-GENDISK Study. 査読

    Kim YW, Kim YJ, Cheong HS, Shiga Y, Hashimoto K, Song YJ, Kim SH, Choi HJ, Nishiguchi KM, Kawai Y, Nagasaki M, Nakazawa T, Park KH, Kim DM, Jeoung JW

    Scientific reports   10 ( 1 )   221   2020年1月

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    記述言語:その他  

    Exploring the Novel Susceptibility Gene Variants for Primary Open-Angle Glaucoma in East Asian Cohorts: The GLAU-GENDISK Study.

    DOI: 10.1038/s41598-019-57066-7

  • 尿酸値の失われた遺伝率は、レアバリアントがかなりの部分を説明する

    三澤 計治, 長谷川 嵩矩, 三島 英換, Jutabha Promsuk, 大内 基司, 小島 要, 河合 洋介, 長崎 正朗, 安西 尚彦

    日本痛風・核酸代謝学会総会プログラム抄録集   53回   66 - 66   2020年1月

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    記述言語:日本語  

  • Study profile of The Tohoku Medical Megabank Community-Based Cohort Study. 査読

    Atsushi Hozawa, Kozo Tanno, Naoki Nakaya, Tomohiro Nakamura, Naho Tsuchiya, Takumi Hirata, Akira Narita, Mana Kogure, Kotaro Nochioka, Ryohei Sasaki, Nobuyuki Takanashi, Kotaro Otsuka, Kiyomi Sakata, Shinichi Kuriyama, Masahiro Kikuya, Osamu Tanabe, Junichi Sugawara, Kichiya Suzuki, Yoichi Suzuki, Eiichi N Kodama, Nobuo Fuse, Hideyasu Kiyomoto, Hiroaki Tomita, Akira Uruno, Yohei Hamanaka, Hirohito Metoki, Mami Ishikuro, Taku Obara, Tomoko Kobayashi, Kazuyuki Kitatani, Takako Takai-Igarashi, Soichi Ogishima, Mamoru Satoh, Hideki Ohmomo, Akito Tsuboi, Shinichi Egawa, Tadashi Ishii, Kiyoshi Ito, Sadayoshi Ito, Yasuyuki Taki, Naoko Minegishi, Naoto Ishii, Masao Nagasaki, Kazuhiko Igarashi, Seizo Koshiba, Ritsuko Shimizu, Gen Tamiya, Keiko Nakayama, Hozumi Motohashi, Jun Yasuda, Atsushi Shimizu, Tsuyoshi Hachiya, Yuh Shiwa, Teiji Tominaga, Hiroshi Tanaka, Kotaro Oyama, Ryoichi Tanaka, Hiroshi Kawame, Akimune Fukushima, Yasushi Ishigaki, Tomoharu Tokutomi, Noriko Osumi, Tadao Kobayashi, Fuji Nagami, Hiroaki Hashizume, Tomohiro Arai, Yoshio Kawaguchi, Shinichi Higuchi, Masaki Sakaida, Ryujin Endo, Satoshi Nishizuka, Ichiro Tsuji, Jiro Hitomi, Motoyuki Nakamura, Kuniaki Ogasawara, Nobuo Yaegashi, Kengo Kinoshita, Shigeo Kure, Akio Sakai, Seiichiro Kobayashi, Kenji Sobue, Makoto Sasaki, Masayuki Yamamoto

    Journal of epidemiology   31 ( 1 )   65 - 76   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BackgroundWe established a community-based cohort study to assess the long-term impact of the Great East Japan Earthquake on disaster victims and gene-environmental interactions on the incidence of major diseases such as cancer and cardiovascular diseases.MethodsWe asked participants to join our cohort in the health check-up settings and assessment center based settings. Inclusion criteria was aged 20 years or over and living in Miyagi or Iwate Prefecture. We obtained information on lifestyle, effect of disaster, blood, and urine information (Type 1 survey), and some detailed measurements (Type 2 survey), for example, carotid echography, calcaneal ultrasound bone mineral density, and so on. All participants agreed to measure genome information and to distribute their information widely.ResultsAs a result, 87,865 gave their informed consent to join our study. Participation rate at health check-up site was about 70%. The participants with Type 1 survey were more likely to have psychological distress than those of Type 2 survey, and women were more likely to have psychological distress than men. Additionally, coastal residents were more likely to have higher degrees of psychological distress than inland residents regardless of sex.ConclusionThis cohort comprised large sample size and it contains information on disaster, genome information, and metabolome information. This cohort also had several detailed measurements. Using this cohort enabled us to clarify the long-term effect of disaster and also to establish personalized prevention based on genome, metabolome, and other omics information.

    DOI: 10.2188/jea.JE20190271

  • A low-frequency IL4R locus variant in Japanese patients with intravenous immunoglobulin therapy-unresponsive Kawasaki disease 査読

    Yuji Amano, Yohei Akazawa, Jun Yasuda, Kazuhisa Yoshino, Katsuhiko Kojima, Norimoto Kobayashi, Satoshi Matsuzaki, Masao Nagasaki, Yosuke Kawai, Naoko Minegishi, Noriko Ishida, Noriko Motoki, Akira Hachiya, Yozo Nakazawa, Masayuki Yamamoto, Kenichi Koike, Toshikazu Takeshita

    Pediatric Rheumatology   17 ( 1 )   34   2019年12月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/s12969-019-0337-2

  • Construction of JRG (Japanese reference genome) with single-molecule real-time sequencing 査読

    Masao Nagasaki, Yoko Kuroki, Tomoko F. Shibata, Fumiki Katsuoka, Takahiro Mimori, Yosuke Kawai, Naoko Minegishi, Atsushi Hozawa, Shinichi Kuriyama, Yoichi Suzuki, Hiroshi Kawame, Fuji Nagami, Takako Takai-Igarashi, Soichi Ogishima, Kaname Kojima, Kazuharu Misawa, Osamu Tanabe, Nobuo Fuse, Hiroshi Tanaka, Nobuo Yaegashi, Kengo Kinoshita, Shiego Kure, Jun Yasuda, Masayuki Yamamoto

    Human Genome Variation   6   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    © 2019, The Author(s). In recent genome analyses, population-specific reference panels have indicated important. However, reference panels based on short-read sequencing data do not sufficiently cover long insertions. Therefore, the nature of long insertions has not been well documented. Here, we assembled a Japanese genome using single-molecule real-time sequencing data and characterized insertions found in the assembled genome. We identified 3691 insertions ranging from 100 bps to ~10,000 bps in the assembled genome relative to the international reference sequence (GRCh38). To validate and characterize these insertions, we mapped short-reads from 1070 Japanese individuals and 728 individuals from eight other populations to insertions integrated into GRCh38. With this result, we constructed JRGv1 (Japanese Reference Genome version 1) by integrating the 903 verified insertions, totaling 1,086,173 bases, shared by at least two Japanese individuals into GRCh38. We also constructed decoyJRGv1 by concatenating 3559 verified insertions, totaling 2,536,870 bases, shared by at least two Japanese individuals or by six other assemblies. This assembly improved the alignment ratio by 0.4% on average. These results demonstrate the importance of refining the reference assembly and creating a population-specific reference genome. JRGv1 and decoyJRGv1 are available at the JRG website.

    DOI: 10.1038/s41439-019-0057-7

  • CD45+CD326+ Cells are Predictive of Poor Prognosis in Non-Small Cell Lung Cancer Patients. 査読 国際誌

    Kota Ishizawa, Mie Yamanaka, Yuriko Saiki, Eisaku Miyauchi, Shinichi Fukushige, Tetsuya Akaishi, Atsuko Asao, Takahiro Mimori, Ryota Saito, Yutaka Tojo, Riu Yamashita, Michiaki Abe, Akira Sakurada, Nhu-An Pham, Ming Li, Yoshinori Okada, Tadashi Ishii, Naoto Ishii, Seiichi Kobayashi, Masao Nagasaki, Masakazu Ichinose, Ming-Sound Tsao, Akira Horii

    Clinical cancer research : an official journal of the American Association for Cancer Research   25 ( 22 )   6756 - 6763   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: The epithelial-to-mesenchymal transition, the major process by which some cancer cells convert from an epithelial phenotype to a mesenchymal one, has been suggested to drive chemo-resistance and/or metastasis in patients with cancer. However, only a few studies have demonstrated the presence of CD45/CD326 doubly-positive cells (CD45/CD326 DPC) in cancer. We deployed a combination of cell surface markers to elucidate the phenotypic heterogeneity in non-small cell lung cancer (NSCLC) cells and identified a new subpopulation that is doubly-positive for epithelial and non-epithelial cell-surface markers in both NSCLC cells and patients' malignant pleural effusions. EXPERIMENTAL DESIGN: We procured a total of 39 patients' samples, solid fresh lung cancer tissues from 21 patients and malignant pleural effusion samples from 18 others, and used FACS and fluorescence microscopy to check their surface markers. We also examined the EGFR mutations in patients with known acquired EGFR mutations. RESULTS: Our data revealed that 0.4% to 17.9% of the solid tumor tissue cells and a higher percentage of malignant pleural effusion cells harbored CD45/CD326 DPC expressing both epithelial and nonepithelial surface markers. We selected 3 EGFR mutation patients and genetically confirmed that the newly identified cell population really originated from cancer cells. We also found that higher proportions of CD45/CD326 DPC are significantly associated with poor prognosis. CONCLUSIONS: In conclusion, varying percentages of CD45/CD326 DPC exist in both solid cancer tissue and malignant pleural effusion in patients with NSCLC. This CD45/CD326 doubly-positive subpopulation can be an important key to clinical management of patients with NSCLC.

    DOI: 10.1158/1078-0432.CCR-19-0545

  • Correction to: High-resolution melt analysis enables simple genotyping of complicated polymorphisms of codon 18 rendering the NUDT15 diplotype. 査読

    Kakuta Y, Izumiyama Y, Okamoto D, Nakano T, Ichikawa R, Naito T, Moroi R, Kuroha M, Kanazawa Y, Kimura T, Shiga H, Kudo H, Minegishi N, Kawai Y, Tokunaga K, Nagasaki M, Kinouchi Y, Suzuki Y, Masamune A, MENDEL study group

    Journal of gastroenterology   55 ( 1 )   67 - 77   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Correction to: High-resolution melt analysis enables simple genotyping of complicated polymorphisms of codon 18 rendering the NUDT15 diplotype.
    Background The genetic variants of NUDT15 have been verified to induce adverse events (AEs) of thiopurines. Codon 139 variants are frequently observed in Asians, while multiple variants are seen in codon 18 which also cause AEs including the European ancestry. The purpose of this study is to establish a technique capable of the simple genotyping of NUDT15 codon 18 and to evaluate its efficacy. Methods A high-resolution melt (HRM) technique is performed to simply determine genotypes. The accuracy of HRM analysis was evaluated with DNAs from 1245 Japanese patients with inflammatory bowel diseases. Subsequently, another group of 572 patients was analyzed to verify the method. The diplotypes and the frequency of their AEs were estimated on the basis of codon 18 and 139 genotypes. Results The HRM analysis enabled the correct identification of the three main genotypes, ref/ref, ref/ins, and ref/V18I, in 1236 of 1241 cases. All rare genotypes including ref/del were identified as the impossible-to-determine group, the proper diagnosis rate was 99.6%. In the verification test using other samples, the diagnosis rate was 99.7%. By estimating diplotypes using both codon 18 and 139 genotypes, 2.74% and 2.13% of Japanese patients with Arg/Arg and Arg/Cys of codon 139 have a lower enzymatic activity of NUDT15 and a higher risk for adverse responses than those estimated by codon 139 genotypes alone. Conclusions Our study showed that HRM method enables simple genotyping of complicated codon 18 variants essential to haplotype estimation of the NUDT15.

    DOI: 10.1007/s00535-019-01646-x

  • High-resolution melt analysis enables simple genotyping of complicated polymorphisms of codon 18 rendering the NUDT15 diplotype. 査読

    Kakuta Y, Izumiyama Y, Okamoto D, Nakano T, Ichikawa R, Naito T, Moroi R, Kuroha M, Kanazawa Y, Kimura T, Shiga H, Kudo H, Minegishi N, Kawai Y, Tokunaga K, Nagasaki M, Kinouchi Y, Suzuki Y, Masasmune A, MENDEL study group

    Journal of gastroenterology   55 ( 1 )   67 - 77   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    High-resolution melt analysis enables simple genotyping of complicated polymorphisms of codon 18 rendering the NUDT15 diplotype.
    Background The genetic variants of NUDT15 have been verified to induce adverse events (AEs) of thiopurines. Codon 139 variants are frequently observed in Asians, while multiple variants are seen in codon 18 which also cause AEs including the European ancestry. The purpose of this study is to establish a technique capable of the simple genotyping of NUDT15 codon 18 and to evaluate its efficacy. Methods A high-resolution melt (HRM) technique is performed to simply determine genotypes. The accuracy of HRM analysis was evaluated with DNAs from 1245 Japanese patients with inflammatory bowel diseases. Subsequently, another group of 572 patients was analyzed to verify the method. The diplotypes and the frequency of their AEs were estimated on the basis of codon 18 and 139 genotypes. Results The HRM analysis enabled the correct identification of the three main genotypes, ref/ref, ref/ins, and ref/V18I, in 1236 of 1241 cases. All rare genotypes including ref/del were identified as the impossible-to-determine group, the proper diagnosis rate was 99.6%. In the verification test using other samples, the diagnosis rate was 99.7%. By estimating diplotypes using both codon 18 and 139 genotypes, 2.74% and 2.13% of Japanese patients with Arg/Arg and Arg/Cys of codon 139 have a lower enzymatic activity of NUDT15 and a higher risk for adverse responses than those estimated by codon 139 genotypes alone. Conclusions Our study showed that HRM method enables simple genotyping of complicated codon 18 variants essential to haplotype estimation of the NUDT15.

    DOI: 10.1007/s00535-019-01638-x

  • Genome-wide association meta-analysis and Mendelian randomization analysis confirm the influence of ALDH2 on sleep durationin the Japanese population. 査読 国際誌

    Takeshi Nishiyama, Masahiro Nakatochi, Atsushi Goto, Motoki Iwasaki, Tsuyoshi Hachiya, Yoichi Sutoh, Atsushi Shimizu, Chaochen Wang, Hideo Tanaka, Miki Watanabe, Akihiro Hosono, Yuya Tamai, Tamaki Yamada, Taiki Yamaji, Norie Sawada, Kentaro Fukumoto, Kotaro Otsuka, Kozo Tanno, Hiroaki Tomita, Kaname Kojima, Masao Nagasaki, Atsushi Hozawa, Asahi Hishida, Tae Sasakabe, Yuichiro Nishida, Megumi Hara, Hidemi Ito, Isao Oze, Yohko Nakamura, Haruo Mikami, Rie Ibusuki, Toshiro Takezaki, Teruhide Koyama, Nagato Kuriyama, Kaori Endoh, Kiyonori Kuriki, Tanvir C Turin, Takashima Naoyuki, Sakurako Katsuura-Kamano, Hirokazu Uemura, Rieko Okada, Sayo Kawai, Mariko Naito, Yukihide Momozawa, Michiaki Kubo, Makoto Sasaki, Masayuki Yamamoto, Shoichiro Tsugane, Kenji Wakai, Sadao Suzuki

    Sleep   42 ( 6 )   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Usual sleep duration has substantial heritability and is associated with various physical and psychiatric conditions as well as mortality. However, for its genetic locus, only PAX8 and VRK2 have been replicated in previous genome-wide association studies (GWAS). We conducted a GWAS meta-analysis of self-reported usual sleep duration using three population-based cohorts totaling 31 230 Japanese individuals. A genome-wide significant locus was identified at 12q24 (p-value < 5.0 × 10-8). Subsequently, a functional variant in the ALDH2 locus, rs671, was replicated in an independent sample of 5140 Japanese individuals (p-value = 0.004). The association signal, however, disappeared after adjusting for alcohol consumption, indicating the possibility that the rs671 genotype modifies sleep duration via alcohol consumption. This hypothesis explained a modest genetic correlation observed between sleep duration and alcohol consumption (rG = 0.23). A Mendelian randomization analysis using rs671 and other variants as instrumental variables confirmed this by showing a causal effect of alcohol consumption, but not of coffee consumption on sleep duration. Another genome-wide significant locus was identified at 5q33 after adjusting for drinking frequency. However, this locus was not replicated, nor was the PAX8 and VRK2. Our study has confirmed that a functional ALDH2 variant, rs671, most strongly influences on usual sleep duration possibly via alcohol consumption in the Japanese population, and presumably in East Asian populations. This highlights the importance of considering the involvement of alcohol consumption in future GWAS of usual sleep duration, even in non-East Asian populations, where rs671 is monomorphic.

    DOI: 10.1093/sleep/zsz046

  • 3.5KJPNv2: an allele frequency panel of 3552 Japanese individuals including the X chromosome. 査読 国際誌

    Shu Tadaka, Fumiki Katsuoka, Masao Ueki, Kaname Kojima, Satoshi Makino, Sakae Saito, Akihito Otsuki, Chinatsu Gocho, Mika Sakurai-Yageta, Inaho Danjoh, Ikuko N Motoike, Yumi Yamaguchi-Kabata, Matsuyuki Shirota, Seizo Koshiba, Masao Nagasaki, Naoko Minegishi, Atsushi Hozawa, Shinichi Kuriyama, Atsushi Shimizu, Jun Yasuda, Nobuo Fuse, Gen Tamiya, Masayuki Yamamoto, Kengo Kinoshita

    Human genome variation   6   28 - 28   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The first step towards realizing personalized healthcare is to catalog the genetic variations in a population. Since the dissemination of individual-level genomic information is strictly controlled, it will be useful to construct population-level allele frequency panels with easy-to-use interfaces. In the Tohoku Medical Megabank Project, we sequenced nearly 4000 individuals from a Japanese population and constructed an allele frequency panel of 3552 individuals after removing related samples. The panel is called the 3.5KJPNv2. It was constructed by using a standard pipeline including the 1KGP and gnomAD algorithms to reduce technical biases and to allow comparisons to other populations. Our database is the first large-scale panel providing the frequencies of variants present on the X chromosome and on the mitochondria in the Japanese population. All the data are available on our original database at https://jmorp.megabank.tohoku.ac.jp.

    DOI: 10.1038/s41439-019-0059-5

  • A 12-kb structural variation in progressive myoclonic epilepsy was newly identified by long-read whole-genome sequencing. 査読 国際誌

    Takeshi Mizuguchi, Takeshi Suzuki, Chihiro Abe, Ayako Umemura, Katsushi Tokunaga, Yosuke Kawai, Minoru Nakamura, Masao Nagasaki, Kengo Kinoshita, Yasunobu Okamura, Satoko Miyatake, Noriko Miyake, Naomichi Matsumoto

    Journal of human genetics   64 ( 5 )   359 - 368   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We report a family with progressive myoclonic epilepsy who underwent whole-exome sequencing but was negative for pathogenic variants. Similar clinical courses of a devastating neurodegenerative phenotype of two affected siblings were highly suggestive of a genetic etiology, which indicates that the survey of genetic variation by whole-exome sequencing was not comprehensive. To investigate the presence of a variant that remained unrecognized by standard genetic testing, PacBio long-read sequencing was performed. Structural variant (SV) detection using low-coverage (6×) whole-genome sequencing called 17,165 SVs (7,216 deletions and 9,949 insertions). Our SV selection narrowed down potential candidates to only five SVs (two deletions and three insertions) on the genes tagged with autosomal recessive phenotypes. Among them, a 12.4-kb deletion involving the CLN6 gene was the top candidate because its homozygous abnormalities cause neuronal ceroid lipofuscinosis. This deletion included the initiation codon and was found in a GC-rich region containing multiple repetitive elements. These results indicate the presence of a causal variant in a difficult-to-sequence region and suggest that such variants that remain enigmatic after the application of current whole-exome sequencing technology could be uncovered by unbiased application of long-read whole-genome sequencing.

    DOI: 10.1038/s10038-019-0569-5

  • A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn's Disease in Japanese Individuals. 査読 国際誌

    Yoichi Kakuta, Yosuke Kawai, Takeo Naito, Atsushi Hirano, Junji Umeno, Yuta Fuyuno, Zhenqiu Liu, Dalin Li, Takeru Nakano, Yasuhiro Izumiyama, Ryo Ichikawa, Daisuke Okamoto, Hiroshi Nagai, Shin Matsumoto, Katsutoshi Yamamoto, Naonobu Yokoyama, Hirofumi Chiba, Yusuke Shimoyama, Motoyuki Onodera, Rintaro Moroi, Masatake Kuroha, Yoshitake Kanazawa, Tomoya Kimura, Hisashi Shiga, Katsuya Endo, Kenichi Negoro, Jun Yasuda, Motohiro Esaki, Katsushi Tokunaga, Minoru Nakamura, Takayuki Matsumoto, Dermot P B McGovern, Masao Nagasaki, Yoshitaka Kinouchi, Tooru Shimosegawa, Atsushi Masamune

    Journal of Crohn's & colitis   13 ( 5 )   648 - 658   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND AND AIMS: Genome-wide association studies [GWASs] of European populations have identified numerous susceptibility loci for Crohn's disease [CD]. Susceptibility genes differ by ethnicity, however, so GWASs specific for Asian populations are required. This study aimed to clarify the Japanese-specific genetic background for CD by a GWAS using the Japonica array [JPA] and subsequent imputation with the 1KJPN reference panel. METHODS: Two independent Japanese case/control sets (Tohoku region [379 CD patients, 1621 controls] and Kyushu region [334 CD patients, 462 controls]) were included. GWASs were performed separately for each population, followed by a meta-analysis. Two additional replication sets [254 + 516 CD patients and 287 + 565 controls] were analysed for top hit single nucleotide polymorphisms [SNPs] from novel genomic regions. RESULTS: Genotype data of 4 335 144 SNPs from 713 Japanese CD patients and 2083 controls were analysed. SNPs located in TNFSF15 (rs78898421, Pmeta = 2.59 × 10-26, odds ratio [OR] = 2.10), HLA-DQB1 [rs184950714, pmeta = 3.56 × 10-19, OR = 2.05], ZNF365, and 4p14 loci were significantly associated with CD in Japanese individuals. Replication analyses were performed for four novel candidate loci [p <1 × 10-6], and rs488200 located upstream of RAP1A was significantly associated with CD [pcombined = 4.36 × 10-8, OR = 1.31]. Transcriptome analysis of CD4+ effector memory T cells from lamina propria mononuclear cells of CD patients revealed a significant association of rs488200 with RAP1A expression. CONCLUSIONS: RAP1A is a novel susceptibility locus for CD in the Japanese population.

    DOI: 10.1093/ecco-jcc/jjy197

  • Construction of full-length Japanese reference panel of class I HLA genes with single-molecule, real-time sequencing 査読

    Takahiro Mimori, Jun Yasuda, Yoko Kuroki, Tomoko F. Shibata, Fumiki Katsuoka, Sakae Saito, Naoki Nariai, Akira Ono, Naomi Nakai-Inagaki, Kazuharu Misawa, Keiko Tateno, Yosuke Kawai, Nobuo Fuse, Atsushi Hozawa, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Kichiya Suzuki, Kengo Kinoshita, Masao Nagasaki, Masayuki Yamamoto

    The Pharmacogenomics Journal   19 ( 2 )   136 - 146   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41397-017-0010-4

  • Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals. 査読 国際誌

    Yamaguchi-Kabata Y, Yasuda J, Uruno A, Shimokawa K, Koshiba S, Suzuki Y, Fuse N, Kawame H, Tadaka S, Nagasaki M, Kojima K, Katsuoka F, Kumada K, Tanabe O, Tamiya G, Yaegashi N, Kinoshita K, Yamamoto M, Kure S, Tohoku Medical Megabank Project, Study Group

    Human genetics   138 ( 4 )   389 - 409   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals.
    Incidence rates of Mendelian diseases vary among ethnic groups, and frequencies of variant types of causative genes also vary among human populations. In this study, we examined to what extent we can predict population frequencies of recessive disorders from genomic data, and explored better strategies for variant interpretation and classification. We used a whole-genome reference panel from 3552 general Japanese individuals constructed by the Tohoku Medical Megabank Organization (ToMMo). Focusing on 32 genes for 17 congenital metabolic disorders included in newborn screening (NBS) in Japan, we identified reported and predicted pathogenic variants through variant annotation, interpretation, and multiple ways of classifications. The estimated carrier frequencies were compared with those from the Japanese NBS data based on 1,949,987 newborns from a previous study. The estimated carrier frequency based on genomic data with a recent guideline of variant interpretation for the PAH gene, in which defects cause hyperphenylalaninemia (HPA) and phenylketonuria (PKU), provided a closer estimate to that by the observed incidence than the other methods. In contrast, the estimated carrier frequencies for SLC25A13, which causes citrin deficiency, were much higher compared with the incidence rate. The results varied greatly among the 11 NBS diseases with single responsible genes; the possible reasons for departures from the carrier frequencies by reported incidence rates were discussed. Of note, (1) the number of pathogenic variants increases by including additional lines of evidence, (2) common variants with mild effects also contribute to the actual frequency of patients, and (3) penetrance of each variant remains unclear.

    DOI: 10.1007/s00439-019-01998-7

  • Genome analyses for the Tohoku Medical Megabank Project towards establishment of personalized healthcare. 査読 国際誌

    Jun Yasuda, Kengo Kinoshita, Fumiki Katsuoka, Inaho Danjoh, Mika Sakurai-Yageta, Ikuko N Motoike, Yoko Kuroki, Sakae Saito, Kaname Kojima, Matsuyuki Shirota, Daisuke Saigusa, Akihito Otsuki, Junko Kawashima, Yumi Yamaguchi-Kabata, Shu Tadaka, Yuichi Aoki, Takahiro Mimori, Kazuki Kumada, Jin Inoue, Satoshi Makino, Miho Kuriki, Nobuo Fuse, Seizo Koshiba, Osamu Tanabe, Masao Nagasaki, Gen Tamiya, Ritsuko Shimizu, Takako Takai-Igarashi, Soichi Ogishima, Atsushi Hozawa, Shinichi Kuriyama, Junichi Sugawara, Akito Tsuboi, Hideyasu Kiyomoto, Tadashi Ishii, Hiroaki Tomita, Naoko Minegishi, Yoichi Suzuki, Kichiya Suzuki, Hiroshi Kawame, Hiroshi Tanaka, Yasuyuki Taki, Nobuo Yaegashi, Shigeo Kure, Fuji Nagami, Kenjiro Kosaki, Yoichi Sutoh, Tsuyoshi Hachiya, Atsushi Shimizu, Makoto Sasaki, Masayuki Yamamoto

    Journal of biochemistry   165 ( 2 )   139 - 158   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Personalized healthcare (PHC) based on an individual's genetic make-up is one of the most advanced, yet feasible, forms of medical care. The Tohoku Medical Megabank (TMM) Project aims to combine population genomics, medical genetics and prospective cohort studies to develop a critical infrastructure for the establishment of PHC. To date, a TMM CommCohort (adult general population) and a TMM BirThree Cohort (birth+three-generation families) have conducted recruitments and baseline surveys. Genome analyses as part of the TMM Project will aid in the development of a high-fidelity whole-genome Japanese reference panel, in designing custom single-nucleotide polymorphism (SNP) arrays specific to Japanese, and in estimation of the biological significance of genetic variations through linked investigations of the cohorts. Whole-genome sequencing from >3,500 unrelated Japanese and establishment of a Japanese reference genome sequence from long-read data have been done. We next aim to obtain genotype data for all TMM cohort participants (>150,000) using our custom SNP arrays. These data will help identify disease-associated genomic signatures in the Japanese population, while genomic data from TMM BirThree Cohort participants will be used to improve the reference genome panel. Follow-up of the cohort participants will allow us to test the genetic markers and, consequently, contribute to the realization of PHC.

    DOI: 10.1093/jb/mvy096

  • NFKB1 and MANBA Confer Disease Susceptibility to Primary Biliary Cholangitis via Independent Putative Primary Functional Variants 査読 国際誌

    Hitomi Yuki, Nakatani Ken, Kojima Kaname, Nishida Nao, Kawai Yosuke, Kawashima Minae, Aiba Yoshihiro, Nagasaki Masao, Nakamura Minoru, Tokunaga Katsushi

    CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY   7 ( 3 )   515 - 532   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    NFKB1 and MANBA Confer Disease Susceptibility to Primary Biliary Cholangitis via Independent Putative Primary Functional Variants
    BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is a chronic and cholestatic liver disease that eventually leads to cirrhosis and hepatic failure. We recently identified several susceptibility genes included NFKB1 and MANBA for PBC in the Japanese population by genome-wide association study. However, the primary functional variants in the NFKB1/MANBA region and the molecular mechanism for conferring disease susceptibility to PBC have not yet been clarified. METHODS: We performed high-density association mapping based on a single-nucleotide polymorphism (SNP) imputation analysis, using data from a whole-genome sequence reference panel of 1070 Japanese individuals and the previous genome-wide association study (1389 PBC patients, 1508 healthy controls). Among SNPs (P < 5.0 × 10-7) in the NFKB1/MANBA region, putative primary functional variants and the molecular mechanism for conferring disease susceptibility to PBC were identified by in silico/in vitro functional analysis. RESULTS: Among the SNPs in the NFKB1/MANBA region, rs17032850 and rs227361, which changed the binding of transcription factors lymphoid enhancer-binding factor 1 (LEF-1) and retinoid X receptor α (RXRα), respectively, were identified as putative primary functional variants that regulate gene expression. In addition, expression-quantitative trait locus data and gene editing using a clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system supported the potential role of rs17032850 and rs227361 in regulating NFKB1 and MANBA expression, respectively. CONCLUSIONS: We identified independent putative primary functional variants in NFKB1/MANBA and showed the distinct molecular mechanism by which each putative primary functional variant conferred susceptibility to PBC. Our approach was useful to dissect the pathogenesis not only of PBC, but also other digestive diseases in which NFKB1/MANBA has been reported as a susceptibility locus.

    DOI: 10.1016/j.jcmgh.2018.11.006

  • Correction: Allele-specific DNA methylation of disease susceptibility genes in Japanese patients with inflammatory bowel disease. 査読 国際誌

    Chiba H, Kakuta Y, Kinouchi Y, Kawai Y, Watanabe K, Nagao M, Naito T, Onodera M, Moroi R, Kuroha M, Kanazawa Y, Kimura T, Shiga H, Endo K, Negoro K, Nagasaki M, Unno M, Shimosegawa T

    PloS one   14 ( 2 )   e0212148   2019年2月

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    記述言語:英語  

    Correction: Allele-specific DNA methylation of disease susceptibility genes in Japanese patients with inflammatory bowel disease.
    [This corrects the article DOI: 10.1371/journal.pone.0194036.].

    DOI: 10.1371/journal.pone.0212148

  • Maternity Log study: a longitudinal lifelog monitoring and multiomics analysis for the early prediction of complicated pregnancy. 査読

    Sugawara J, Ochi D, Yamashita R, Yamauchi T, Saigusa D, Wagata M, Obara T, Ishikuro M, Tsunemoto Y, Harada Y, Shibata T, Mimori T, Kawashima J, Katsuoka F, Igarashi-Takai T, Ogishima S, Metoki H, Hashizume H, Fuse N, Minegishi N, Koshiba S, Tanabe O, Kuriyama S, Kinoshita K, Kure S, Yaegashi N, Yamamoto M, Hiyama S, Nagasaki M

    BMJ open   9 ( 2 )   e025939   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Maternity Log study: a longitudinal lifelog monitoring and multiomics analysis for the early prediction of complicated pregnancy.
    Purpose A prospective cohort study for pregnant women, the Maternity Log study, was designed to construct a time-course high-resolution reference catalogue of bioinformatic data in pregnancy and explore the associations between genomic and environmental factors and the onset of pregnancy complications, such as hypertensive disorders of pregnancy, gestational diabetes mellitus and preterm labour, using continuous lifestyle monitoring combined with multiomics data on the genome, transcriptome, proteome, metabolome and microbiome.Participants Pregnant women were recruited at the timing of first routine antenatal visits at Tohoku University Hospital, Sendai, Japan, between September 2015 and November 2016. Of the eligible women who were invited, 65.4% agreed to participate, and a total of 302 women were enrolled. The inclusion criteria were age >= 20 years and the ability to access the internet using a smartphone in the Japanese language.Findings to date Study participants uploaded daily general health information including quality of sleep, condition of bowel movements and the presence of nausea, pain and uterine contractions. Participants also collected physiological data, such as body weight, blood pressure, heart rate and body temperature, using multiple home healthcare devices. The mean upload rate for each lifelog item was ranging from 67.4% (fetal movement) to 85.3% (physical activity), and the total number of data points was over 6 million. Biospecimens, including maternal plasma, serum, urine, saliva, dental plaque and cord blood, were collected for multiomics analysis.Future plans Lifelog and multiomics data will be used to construct a time-course high-resolution reference catalogue of pregnancy. The reference catalogue will allow us to discover relationships among multidimensional phenotypes and novel risk markers in pregnancy for the future personalised early prediction of pregnancy complications.

    DOI: 10.1136/bmjopen-2018-025939

  • POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33. 査読

    Hitomi Y, Ueno K, Kawai Y, Nishida N, Kojima K, Kawashima M, Aiba Y, Nakamura H, Kouno H, Kouno H, Ohta H, Sugi K, Nikami T, Yamashita T, Katsushima S, Komeda T, Ario K, Naganuma A, Shimada M, Hirashima N, Yoshizawa K, Makita F, Furuta K, Kikuchi M, Naeshiro N, Takahashi H, Mano Y, Yamashita H, Matsushita K, Tsunematsu S, Yabuuchi I, Nishimura H, Shimada Y, Yamauchi K, Komatsu T, Sugimoto R, Sakai H, Mita E, Koda M, Nakamura Y, Kamitsukasa H, Sato T, Nakamuta M, Masaki N, Takikawa H, Tanaka A, Ohira H, Zeniya M, Abe M, Kaneko S, Honda M, Arai K, Arinaga-Hino T, Hashimoto E, Taniai M, Umemura T, Joshita S, Nakao K, Ichikawa T, Shibata H, Takaki A, Yamagiwa S, Seike M, Sakisaka S, Takeyama Y, Harada M, Senju M, Yokosuka O, Kanda T, Ueno Y, Ebinuma H, Himoto T, Murata K, Shimoda S, Nagaoka S, Abiru S, Komori A, Migita K, Ito M, Yatsuhashi H, Maehara Y, Uemoto S, Kokudo N, Nagasaki M, Tokunaga K, Nakamura M

    Scientific reports   9 ( 1 )   102   2019年1月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33.

    DOI: 10.1038/s41598-018-36490-1

  • Susceptibility Loci for Tanning Ability in the Japanese Population Identified by a Genome-Wide Association Study from the Tohoku Medical Megabank Project Cohort Study. 査読

    Shido K, Kojima K, Yamasaki K, Hozawa A, Tamiya G, Ogishima S, Minegishi N, Kawai Y, Tanno K, Suzuki Y, Nagasaki M, Aiba S

    The Journal of investigative dermatology   139 ( 7 )   1605 - 1608.e13   2019年1月

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    記述言語:英語  

    Susceptibility Loci for Tanning Ability in the Japanese Population Identified by a Genome-Wide Association Study from the Tohoku Medical Megabank Project Cohort Study.

    DOI: 10.1016/j.jid.2019.01.015

  • 時系列ライフログと妊娠糖尿病の関連解析

    熊谷 沙津希, 越智 大介, 山内 隆史, 和形 麻衣子, 長崎 正朗, 菅原 準一

    糖尿病と妊娠   18 ( 3 )   S - 115   2018年11月

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    記述言語:日本語  

  • Identification of a two-SNP PLA2R1 Haplotype and HLA-DRB1 Alleles as Primary Risk Associations in Idiopathic Membranous Nephropathy. 査読

    Latt KZ, Honda K, Thiri M, Hitomi Y, Omae Y, Sawai H, Kawai Y, Teraguchi S, Ueno K, Nagasaki M, Mabuchi A, Kaga H, Komatsuda A, Tokunaga K, Noiri E

    Scientific reports   8 ( 1 )   15576   2018年10月

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    記述言語:その他  

    Identification of a two-SNP PLA2R1 Haplotype and HLA-DRB1 Alleles as Primary Risk Associations in Idiopathic Membranous Nephropathy.

    DOI: 10.1038/s41598-018-33612-7

  • Time-Series Filtering for Replicated Observations via a Kernel Approximate Bayesian Computation 査読

    Takanori Hasegawa, Kaname Kojima, Yosuke Kawai, Masao Nagasaki

    IEEE Transactions on Signal Processing   66 ( 23 )   6148 - 6161   2018年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Time-Series Filtering for Replicated Observations via a Kernel Approximate Bayesian Computation

    DOI: 10.1109/TSP.2018.2872864

  • Functional characterization of 40 CYP2B6 allelic variants by assessing efavirenz 8-hydroxylation. 査読 国際誌

    Watanabe T, Saito T, Rico EMG, Hishinuma E, Kumondai M, Maekawa M, Oda A, Saigusa D, Saito S, Yasuda J, Nagasaki M, Minegishi N, Yamamoto M, Yamaguchi H, Mano N, Hirasawa N, Hiratsuka M

    Biochemical pharmacology   156   420 - 430   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Functional characterization of 40 CYP2B6 allelic variants by assessing efavirenz 8-hydroxylation.
    Genetic variations within cytochrome P450 2B6 (CYP2B6) contribute to inter-individual variation in the metabolism of clinically important drugs, including cyclophosphamide, bupropion, methadone and efavirenz (EFZ). In this study, we performed an in vitro analysis of 40 CYP2B6 allelic variant proteins including seven novel variants identified in 1070 Japanese individuals. Wild-type and 39 variant proteins were heterologously expressed in 293FT cells to estimate the kinetic parameters (Km, Vmax, and CLint) of EFZ 8-hydroxylation and 7-ethoxy-4-trifluoromethylcoumarin (7-ETC) O-deethylation activities. The concentrations of CYP2B6 variant holo-enzymes were measured by using carbon monoxide (CO)-reduced difference spectroscopy, and the wild-type and 28 variants showed a peak at 450 nm. The kinetic parameters were measured for the wild-type and 24 variant proteins. The values for the remaining 15 variants could not be determined because the enzymatic activity was not detected at the highest substrate concentration used. Compared to wild-type, six variants showed significantly decreased EFZ 8-hydroxylation CLint values, while these values were significantly increased in another six variants, including CYP2B6.6. Although 7-ETC O-deethylation CLint values of CYP2B6 variants did not differ significantly from that of CYP2B6.1, the CLint ratios obtained for 7-ETC O-deethylation were highly correlated with EFZ 8-hydroxylation. Furthermore, three-dimensional structural modeling analysis was performed to elucidate the mechanism of changes in the kinetics of CYP2B6 variants. Our findings could provide evidence of the specific metabolic activities of the CYP2B6 proteins encoded by these variant alleles.

    DOI: 10.1016/j.bcp.2018.09.010

  • 全ゲノムシークエンス解析を用いた感冒薬関連重症薬疹(CM-SJS/TEN)発症に関わる遺伝要因の網羅的探索

    人見 祐基, Khor Seik-Soon, 上田 真由美, 河合 洋介, 外園 千恵, 木下 茂, 長崎 正朗, 徳永 勝士

    MHC: Major Histocompatibility Complex   25 ( 2Suppl. )   89 - 89   2018年9月

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    記述言語:日本語  

  • NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study. 査読

    Yoichi Kakuta, Yosuke Kawai, Daisuke Okamoto, Tetsuya Takagawa, Kentaro Ikeya, Hirotake Sakuraba, Atsushi Nishida, Shoko Nakagawa, Miki Miura, Takahiko Toyonaga, Kei Onodera, Masaru Shinozaki, Yoh Ishiguro, Shinta Mizuno, Masahiro Takahara, Shunichi Yanai, Ryota Hokari, Tomoo Nakagawa, Hiroshi Araki, Satoshi Motoya, Takeo Naito, Rintaro Moroi, Hisashi Shiga, Katsuya Endo, Taku Kobayashi, Makoto Naganuma, Sakiko Hiraoka, Takayuki Matsumoto, Shiro Nakamura, Hiroshi Nakase, Tadakazu Hisamatsu, Makoto Sasaki, Hiroyuki Hanai, Akira Andoh, Masao Nagasaki, Yoshitaka Kinouchi, Tooru Shimosegawa, Atsushi Masamune, Yasuo Suzuki

    Journal of gastroenterology   53 ( 9 )   1065 - 1078   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Despite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs. METHODS: Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation. RESULTS: We confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E-63, 1.32E-69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E-04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively). CONCLUSIONS: Genotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.

    DOI: 10.1007/s00535-018-1486-7

  • Development and application of a rapid and sensitive genotyping method for pharmacogene variants using the single-stranded tag hybridization chromatographic printed-array strip (STH-PAS). 査読 国際誌

    Kumondai M, Ito A, Hishinuma E, Kikuchi A, Saito T, Takahashi M, Tsukada C, Saito S, Yasuda J, Nagasaki M, Minegishi N, Yamamoto M, Kaneko A, Teramoto I, Kimura M, Hirasawa N, Hiratsuka M

    Drug metabolism and pharmacokinetics   33 ( 6 )   epub - epub   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Development and application of a rapid and sensitive genotyping method for pharmacogene variants using the single-stranded tag hybridization chromatographic printed-array strip (STH-PAS).
    Genetic polymorphisms contribute to inter-individual variability in the metabolism of multiple clinical drugs, including warfarin, thiopurines, primaquine, and aminoglycosides. A rapid and sensitive clinical assessment of various genome biomarkers is, therefore, required to predict the individual responsiveness of each patient to these drugs. In this study, we developed a novel genotyping method for the detection of nine pharmacogene variants that are important in the prediction of drug efficiency and toxicity. This genotyping method uses competitive allele-specific PCR and a single-stranded tag hybridization chromatographic printed-array strip (STH-PAS) that can unambiguously determine the presence or absence of the gene variant by displaying visible blue lines on the chromatographic printed-array strip. Notably, the results of our STH-PAS method were in 100% agreement with those obtained using standard Sanger sequencing and KASP assay genotyping methods for CYP4F2 gene deletion. Moreover, the results were obtained within 90 min, including the PCR amplification and signal detection processes. The sensitive and rapid nature of this novel method make it ideal for clinical genetic testing to predict drug efficacy and toxicity, and in doing so will aid in the development of individualized medicine and better patient care.

    DOI: 10.1016/j.dmpk.2018.08.003

  • Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population. 査読 国際誌

    Xiaoyuan Jia, Tomoko Horinouchi, Yuki Hitomi, Akemi Shono, Seik-Soon Khor, Yosuke Omae, Kaname Kojima, Yosuke Kawai, Masao Nagasaki, Yoshitsugu Kaku, Takayuki Okamoto, Yoko Ohwada, Kazuhide Ohta, Yusuke Okuda, Rika Fujimaru, Ken Hatae, Naonori Kumagai, Emi Sawanobori, Hitoshi Nakazato, Yasufumi Ohtsuka, Koichi Nakanishi, Yuko Shima, Ryojiro Tanaka, Akira Ashida, Koichi Kamei, Kenji Ishikura, Kandai Nozu, Katsushi Tokunaga, Kazumoto Iijima

    Journal of the American Society of Nephrology : JASN   29 ( 8 )   2189 - 2199   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background Nephrotic syndrome is the most common cause of chronic glomerular disease in children. Most of these patients develop steroid-sensitive nephrotic syndrome (SSNS), but the loci conferring susceptibility to childhood SSNS are mainly unknown.Methods We conducted a genome-wide association study (GWAS) in the Japanese population; 224 patients with childhood SSNS and 419 adult healthy controls were genotyped using the Affymetrix Japonica Array in the discovery stage. Imputation for six HLA genes (HLA-A, -C, -B, -DRB1, -DQB1, and -DPB1) was conducted on the basis of Japanese-specific references. We performed genotyping for HLA-DRB1/-DQB1 using a sequence-specific oligonucleotide-probing method on a Luminex platform. Whole-genome imputation was conducted using a phased reference panel of 2049 healthy Japanese individuals. Replication was performed in an independent Japanese sample set including 216 patients and 719 healthy controls. We genotyped candidate single-nucleotide polymorphisms using the DigiTag2 assay.Results The most significant association was detected in the HLA-DR/DQ region and replicated (rs4642516 [minor allele G], combined Pallelic=7.84×10-23; odds ratio [OR], 0.33; 95% confidence interval [95% CI], 0.26 to 0.41; rs3134996 [minor allele A], combined Pallelic=1.72×10-25; OR, 0.29; 95% CI, 0.23 to 0.37). HLA-DRB1*08:02 (Pc=1.82×10-9; OR, 2.62; 95% CI, 1.94 to 3.54) and HLA-DQB1*06:04 (Pc=2.09×10-12; OR, 0.10; 95% CI, 0.05 to 0.21) were considered primary HLA alleles associated with childhood SSNS. HLA-DRB1*08:02-DQB1*03:02 (Pc=7.01×10-11; OR, 3.60; 95% CI, 2.46 to 5.29) was identified as the most significant genetic susceptibility factor.Conclusions The most significant association with childhood SSNS was detected in the HLA-DR/DQ region. Further HLA allele/haplotype analyses should enhance our understanding of molecular mechanisms underlying SSNS.

    DOI: 10.1681/ASN.2017080859

  • Functional Characterization of 21 Allelic Variants of Dihydropyrimidine Dehydrogenase Identified in 1070 Japanese Individuals. 査読 国際誌

    Hishinuma E, Narita Y, Saito S, Maekawa M, Akai F, Nakanishi Y, Yasuda J, Nagasaki M, Yamamoto M, Yamaguchi H, Mano N, Hirasawa N, Hiratsuka M

    Drug metabolism and disposition: the biological fate of chemicals   46 ( 8 )   1083 - 1090   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Functional Characterization of 21 Allelic Variants of Dihydropyrimidine Dehydrogenase Identified in 1070 Japanese Individuals.
    Dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2), encoded by the DPYD gene, is the rate-limiting enzyme in the degradation pathway of endogenous pyrimidine and fluoropyrimidine drugs such as 5-fluorouracil (5-FU). DPD catalyzes the reduction of uracil, thymine, and 5-FU. In Caucasians, DPYD mutations, including DPYD*2A, DPYD*13, c.2846A>T, and c.1129-5923C>G/hapB3, are known to contribute to interindividual variations in the toxicity of 5-FU; however, none of these DPYD polymorphisms has been identified in the Asian population. Recently, 21 DPYD allelic variants, including some novel single-nucleotide variants (SNVs), were identified in 1070 healthy Japanese individuals by analyzing their whole-genome sequences (WGSs), but the functional alterations caused by these variants remain unknown. In this study, in vitro analysis was performed on 22 DPD allelic variants by transiently expressing wild-type DPD and 21 DPD variants in 293FT cells and characterizing their enzymatic activities using 5-FU as a substrate. DPD expression levels and dimeric forms were determined using immunoblotting and blue-native PAGE, respectively. Additionally, the values of three kinetic parameters-the Michaelis constant (Km ), maximum velocity (Vmax ), and intrinsic clearance (CLint = Vmax/Km )-were determined for the reduction of 5-FU. Eleven variants exhibited significantly decreased intrinsic clearance compared with wild-type DPD. Moreover, the band patterns observed in the immunoblots of blue-native gels indicated that DPD dimerization is required for enzymatic activity in DPD. Thus, the detection of rare DPYD variants might facilitate severe adverse effect prediction of 5-FU-based chemotherapy in the Japanese population.

    DOI: 10.1124/dmd.118.081737

  • Regional genetic differences among Japanese populations and performance of genotype imputation using whole-genome reference panel of the Tohoku Medical Megabank Project. 査読 国際誌

    Jun Yasuda, Fumiki Katsuoka, Inaho Danjoh, Yosuke Kawai, Kaname Kojima, Masao Nagasaki, Sakae Saito, Yumi Yamaguchi-Kabata, Shu Tadaka, Ikuko N Motoike, Kazuki Kumada, Mika Sakurai-Yageta, Osamu Tanabe, Nobuo Fuse, Gen Tamiya, Koichiro Higasa, Fumihiko Matsuda, Nobufumi Yasuda, Motoki Iwasaki, Makoto Sasaki, Atsushi Shimizu, Kengo Kinoshita, Masayuki Yamamoto

    BMC genomics   19 ( 1 )   551 - 551   2018年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Genotype imputation from single-nucleotide polymorphism (SNP) genotype data using a haplotype reference panel consisting of thousands of unrelated individuals from populations of interest can help to identify strongly associated variants in genome-wide association studies. The Tohoku Medical Megabank (TMM) project was established to support the development of precision medicine, together with the whole-genome sequencing of 1070 human genomes from individuals in the Miyagi region (Northeast Japan) and the construction of the 1070 Japanese genome reference panel (1KJPN). Here, we investigated the performance of 1KJPN for genotype imputation of Japanese samples not included in the TMM project and compared it with other population reference panels. RESULTS: We found that the 1KJPN population was more similar to other Japanese populations, Nagahama (south-central Japan) and Aki (Shikoku Island), than to East Asian populations in the 1000 Genomes Project other than JPT, suggesting that the large-scale collection (more than 1000) of Japanese genomes from the Miyagi region covered many of the genetic variations of Japanese in mainland Japan. Moreover, 1KJPN outperformed the phase 3 reference panel of the 1000 Genomes Project (1KGPp3) for Japanese samples, and IKJPN showed similar imputation rates for the TMM and other Japanese samples for SNPs with minor allele frequencies (MAFs) higher than 1%. CONCLUSIONS: 1KJPN covered most of the variants found in the samples from areas of the Japanese mainland outside the Miyagi region, implying 1KJPN is representative of the Japanese population's genomes. 1KJPN and successive reference panels are useful genome reference panels for the mainland Japanese population. Importantly, the addition of whole genome sequences not included in the 1KJPN panel improved imputation efficiencies for SNPs with MAFs under 1% for samples from most regions of the Japanese archipelago.

    DOI: 10.1186/s12864-018-4942-0

  • Analysis of Müller glia specific genes and their histone modification using Hes1-promoter driven EGFP expressing mouse. 査読 国際誌

    Ueno K, Iwagawa T, Ochiai G, Koso H, Nakauchi H, Nagasaki M, Suzuki Y, Watanabe S

    Scientific reports   8 ( 1 )   8946 - 8946   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Author Correction: Analysis of Müller glia specific genes and their histone modification using Hes1-promoter driven EGFP expressing mouse.
    A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

    DOI: 10.1038/s41598-018-27041-9

  • 網羅的全ゲノム解析法を駆使した感冒薬関連重症薬疹における疾患感受性遺伝子の同定

    人見 祐基, 上田 真由美, 長崎 正朗, 徳永 勝士

    臨床薬理の進歩   ( 39 )   164 - 170   2018年6月

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    記述言語:日本語  

    感冒薬関連重症薬疹を対象に全エクソーム解析を実施し、ゲノムワイド関連解析から取りこぼされた可能性のある遺伝要因の探索を試みた。眼障害のある感冒薬関連スティーブンス・ジョンソン症候群/中毒性表皮壊死融解症患者117例(男性46例、女性71例、平均41.5±17.1歳)を対象とした。全ゲノムシークエンス解析から得られた一塩基多型(SNP)の遺伝子型情報を比較したところ、有意水準を満たすSNPが2ヶ所以上検出された新規疾患感受性遺伝子として14ヶ所が同定された。次に、GTEX portal databaseを用いた量的形質遺伝子座(e-QTL)解析およびPolyphen2を用いたタンパク産物への影響の検証を実施した。その結果、PDIA6のrs4807、SEC16Bのrs7413442、PNCTのrs2249060などのSNPは、遺伝子発現量との強い関連を示していた。一方、MUC16のrs11670318、F5のrs6027、FAT2のrs1432862などのSNPは、その遺伝子がコードするタンパク産物へ重大な影響を与えていることが予測された。

  • Omics research project on prospective cohort studies from the Tohoku Medical Megabank Project. 査読 国際誌

    Seizo Koshiba, Ikuko Motoike, Daisuke Saigusa, Jin Inoue, Matsuyuki Shirota, Yasutake Katoh, Fumiki Katsuoka, Inaho Danjoh, Atsushi Hozawa, Shinichi Kuriyama, Naoko Minegishi, Masao Nagasaki, Takako Takai-Igarashi, Soichi Ogishima, Nobuo Fuse, Shigeo Kure, Gen Tamiya, Osamu Tanabe, Jun Yasuda, Kengo Kinoshita, Masayuki Yamamoto

    Genes to cells : devoted to molecular & cellular mechanisms   23 ( 6 )   406 - 417   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Population-based prospective cohort studies are indispensable for modern medical research as they provide important knowledge on the influences of many kinds of genetic and environmental factors on the cause of disease. Although traditional cohort studies are mainly conducted using questionnaires and physical examinations, modern cohort studies incorporate omics and genomic approaches to obtain comprehensive physical information, including genetic information. Here, we report the design and midterm results of multi-omics analysis on population-based prospective cohort studies from the Tohoku Medical Megabank (TMM) Project. We have incorporated genomic and metabolomic studies in the TMM cohort study as both metabolome and genome analyses are suitable for high-throughput analysis of large-scale cohort samples. Moreover, an association study between the metabolome and genome show that metabolites are an important intermediate phenotype connecting genetic and lifestyle factors to physical and pathologic phenotypes. We apply our metabolome and genome analyses to large-scale cohort samples in the following studies.

    DOI: 10.1111/gtc.12588

  • NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population. 査読 国際誌

    Nao Nishida, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Kaname Kojima, Yosuke Kawai, Kazuko Ueno, Hitomi Nakamura, Noriyo Yamashiki, Tomohiro Tanaka, Sumito Tamura, Akira Mori, Shintaro Yagi, Yuji Soejima, Tomoharu Yoshizumi, Mitsuhisa Takatsuki, Atsushi Tanaka, Kenichi Harada, Shinji Shimoda, Atsumasa Komori, Susumu Eguchi, Yoshihiko Maehara, Shinji Uemoto, Norihiro Kokudo, Masao Nagasaki, Katsushi Tokunaga, Minoru Nakamura

    Scientific reports   8 ( 1 )   8071 - 8071   2018年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Approximately 10-20% of patients with primary biliary cholangitis (PBC) progress to jaundice stage regardless of treatment with ursodeoxycholic acid and bezafibrate. In this study, we performed a GWAS and a replication study to identify genetic variants associated with jaundice-stage progression in PBC using a total of 1,375 patients (1,202 early-stage and 173 jaundice-stage) in a Japanese population. SNP rs13720, which is located in the 3'UTR of cathepsin Z (CTSZ), showed the strongest association (odds ratio [OR] = 2.15, P = 7.62 × 10-7) with progression to jaundice stage in GWAS. High-density association mapping at the CTSZ and negative elongation factor complex member C/D (NELFCD) loci, which are located within a strong linkage disequilibrium (LD) block, revealed that an intronic SNP of CTSZ, rs163800, was significantly associated with jaundice-stage progression (OR = 2.16, P = 8.57 × 10-8). In addition, eQTL analysis and in silico functional analysis indicated that genotypes of rs163800 or variants in strong LD with rs163800 influence expression levels of both NELFCD and CTSZ mRNA. The present novel findings will contribute to dissect the mechanism of PBC progression and also to facilitate the development of therapies for PBC patients who are resistant to current therapies.

    DOI: 10.1038/s41598-018-26369-6

  • Population-scale whole genome sequencing identifies 271 highly polymorphic short tandem repeats from Japanese population. 査読 国際誌

    Satoshi Hirata, Kaname Kojima, Kazuharu Misawa, Olivier Gervais, Yosuke Kawai, Masao Nagasaki

    Heliyon   4 ( 5 )   e00625 - e00625   2018年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Forensic DNA typing is widely used to identify missing persons and plays a central role in forensic profiling. DNA typing usually uses capillary electrophoresis fragment analysis of PCR amplification products to detect the length of short tandem repeat (STR) markers. Here, we analyzed whole genome data from 1,070 Japanese individuals generated using massively parallel short-read sequencing of 162 paired-end bases. We have analyzed 843,473 STR loci with two to six basepair repeat units and cataloged highly polymorphic STR loci in the Japanese population. To evaluate the performance of the cataloged STR loci, we compared 23 STR loci, widely used in forensic DNA typing, with capillary electrophoresis based STR genotyping results in the Japanese population. Seventeen loci had high correlations and high call rates. The other six loci had low call rates or low correlations due to either the limitations of short-read sequencing technology, the bioinformatics tool used, or the complexity of repeat patterns. With these analyses, we have also purified the suitable 218 STR loci with four basepair repeat units and 53 loci with five basepair repeat units both for short read sequencing and PCR based technologies, which would be candidates to the actual forensic DNA typing in Japanese population.

    DOI: 10.1016/j.heliyon.2018.e00625

  • Identification of somatic mutations in postmortem human brains by whole genome sequencing and their implications for psychiatric disorders. 査読 国際誌

    Masaki Nishioka, Miki Bundo, Junko Ueda, Fumiki Katsuoka, Yukuto Sato, Yoko Kuroki, Takao Ishii, Wataru Ukai, Shigeo Murayama, Eri Hashimoto, Masao Nagasaki, Jun Yasuda, Kiyoto Kasai, Tadafumi Kato, Kazuya Iwamoto

    Psychiatry and clinical neurosciences   72 ( 4 )   280 - 294   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIM: Somatic mutations in the human brain are hypothesized to contribute to the functional diversity of brain cells as well as the pathophysiology of neuropsychiatric diseases. However, there are still few reports on somatic mutations in non-neoplastic human brain tissues. This study attempted to unveil the landscape of somatic mutations in the human brain. METHODS: We explored the landscape of somatic mutations in human brain tissues derived from three individuals with no neuropsychiatric diseases by whole-genome deep sequencing at a depth of around 100. The candidate mutations underwent multi-layered filtering, and were validated by ultra-deep target amplicon sequencing at a depth of around 200 000. RESULTS: Thirty-one somatic mutations were identified in the human brain, demonstrating the utility of whole-genome sequencing of bulk brain tissue. The mutations were enriched in neuron-expressed genes, and two-thirds of the identified somatic single nucleotide variants in the brain tissues were cytosine-to-thymine transitions, half of which were in CpG dinucleotides. CONCLUSION: Our developed filtering and validation approaches will be useful to identify somatic mutations in the human brain. The vulnerability of neuron-expressed genes to mutational events suggests their potential relevance to neuropsychiatric diseases.

    DOI: 10.1111/pcn.12632

  • 日本人原発性胆汁性胆管炎の疾患感受性遺伝子POU2AF1、PRKCBの役割の検討

    相葉 佳洋, 原田 憲一, 伊東 正博, 人見 祐基, 植野 和子, 小森 敦正, 八橋 弘, 長崎 正朗, 徳永 勝士, 中村 稔

    肝臓   59 ( Suppl.1 )   A455 - A455   2018年4月

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    記述言語:日本語  

  • Clinical and genetic risk factors for decreased bone mineral density in Japanese patients with inflammatory bowel disease. 査読 国際誌

    Naito T, Yokoyama N, Kakuta Y, Ueno K, Kawai Y, Onodera M, Moroi R, Kuroha M, Kanazawa Y, Kimura T, Shiga H, Endo K, Nagasaki M, Masamune A, Kinouchi Y, Shimosegawa T

    Journal of gastroenterology and hepatology   33 ( 11 )   epub - epub   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Clinical and genetic risk factors for decreased bone mineral density in Japanese patients with inflammatory bowel disease.
    BACKGROUND AND AIM: Patients with inflammatory bowel disease (IBD) are at a high risk of low bone mineral density (BMD). Reportedly, clinical and genetic factors cause low BMD in Caucasians; however, studies in non-Caucasian populations remain scarce. METHODS: Clinical risk factors for low BMD were investigated in 266 Japanese patients with IBD, and a genome-wide association analysis (GWAS) was performed using linear regression with associated clinical factors as covariates. Genotyping was performed using a population-optimized genotyping array (Japonica array® ). After quality control, the genotype data of 4 384 682 single-nucleotide polymorphisms (SNPs) from 254 patients with IBD were used for GWAS. RESULTS: Body mass index, age, and disease duration were independently associated with the BMD of the femoral neck (P = 1.41E - 13, 1.04E - 5, and 1.58E - 3, respectively), and body mass index and sex were associated with the BMD of the lumbar spine (P = 6.90E - 10 and 6.84E - 3, respectively). In GWAS, 118 and 42 candidate SNPs of the femoral neck and lumbar spine, respectively, were identified. Among 118, 111 candidate SNPs of the femoral neck were located within the SLC22A23 gene, which is a known IBD susceptibility gene (minimum P = 1.42E - 07). Among 42, 18 candidate SNPs of the lumbar spine were located within the MECOM gene, which is associated with osteopenia (minimum P = 5.86E - 07). Interestingly, none of the known loci showed a significant association with BMD. CONCLUSIONS: Although clinical risk factors for low BMD in IBD were similar to those in the general population, genetic risk factors were rather different.

    DOI: 10.1111/jgh.14149

  • Allele-specific DNA methylation of disease susceptibility genes in Japanese patients with inflammatory bowel disease. 査読 国際誌

    Hirofumi Chiba, Yoichi Kakuta, Yoshitaka Kinouchi, Yosuke Kawai, Kazuhiro Watanabe, Munenori Nagao, Takeo Naito, Motoyuki Onodera, Rintaro Moroi, Masatake Kuroha, Yoshitake Kanazawa, Tomoya Kimura, Hisashi Shiga, Katsuya Endo, Kenichi Negoro, Masao Nagasaki, Michiaki Unno, Tooru Shimosegawa

    PloS one   13 ( 3 )   e0194036 - e0194036   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Inflammatory bowel disease (IBD) has an unknown etiology; however, accumulating evidence suggests that IBD is a multifactorial disease influenced by a combination of genetic and environmental factors. The influence of genetic variants on DNA methylation in cis and cis effects on expression have been demonstrated. We hypothesized that IBD susceptibility single-nucleotide polymorphisms (SNPs) regulate susceptibility gene expressions in cis by regulating DNA methylation around SNPs. For this, we determined cis-regulated allele-specific DNA methylation (ASM) around IBD susceptibility genes in CD4+ effector/memory T cells (Tem) in lamina propria mononuclear cells (LPMCs) in patients with IBD and examined the association between the ASM SNP genotype and neighboring susceptibility gene expressions. METHODS: CD4+ effector/memory T cells (Tem) were isolated from LPMCs in 15 Japanese IBD patients (ten Crohn's disease [CD] and five ulcerative colitis [UC] patients). ASM analysis was performed by methylation-sensitive SNP array analysis. We defined ASM as a changing average relative allele score ([Formula: see text]) >0.1 after digestion by methylation-sensitive restriction enzymes. Among SNPs showing [Formula: see text] >0.1, we extracted the probes located on tag-SNPs of 200 IBD susceptibility loci and around IBD susceptibility genes as candidate ASM SNPs. To validate ASM, bisulfite-pyrosequencing was performed. Transcriptome analysis was examined in 11 IBD patients (seven CD and four UC patients). The relation between rs36221701 genotype and neighboring gene expressions were analyzed. RESULTS: We extracted six candidate ASM SNPs around IBD susceptibility genes. The top of [Formula: see text] (0.23) was rs1130368 located on HLA-DQB1. ASM around rs36221701 ([Formula: see text] = 0.14) located near SMAD3 was validated using bisulfite pyrosequencing. The SMAD3 expression was significantly associated with the rs36221701 genotype (p = 0.016). CONCLUSIONS: We confirmed the existence of cis-regulated ASM around IBD susceptibility genes and the association between ASM SNP (rs36221701) genotype and SMAD3 expression, a susceptibility gene for IBD. These results give us supporting evidence that DNA methylation mediates genetic effects on disease susceptibility.

    DOI: 10.1371/journal.pone.0194036

  • Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals. 査読 国際誌

    Yumi Yamaguchi-Kabata, Jun Yasuda, Osamu Tanabe, Yoichi Suzuki, Hiroshi Kawame, Nobuo Fuse, Masao Nagasaki, Yosuke Kawai, Kaname Kojima, Fumiki Katsuoka, Sakae Saito, Inaho Danjoh, Ikuko N Motoike, Riu Yamashita, Seizo Koshiba, Daisuke Saigusa, Gen Tamiya, Shigeo Kure, Nobuo Yaegashi, Yoshio Kawaguchi, Fuji Nagami, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Atsushi Hozawa, Soichi Ogishima, Hideyasu Kiyomoto, Takako Takai-Igarashi, Kengo Kinoshita, Masayuki Yamamoto

    Journal of human genetics   63 ( 2 )   213 - 230   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Clarifying allele frequencies of disease-related genetic variants in a population is important in genomic medicine; however, such data is not yet available for the Japanese population. To estimate frequencies of actionable pathogenic variants in the Japanese population, we examined the reported pathological variants in genes recommended by the American College of Medical Genetics and Genomics (ACMG) in our reference panel of genomic variations, 2KJPN, which was created by whole-genome sequencing of 2049 individuals of the resident cohort of the Tohoku Medical Megabank Project. We searched for pathogenic variants in 2KJPN for 57 autosomal ACMG-recommended genes responsible for 26 diseases and then examined their frequencies. By referring to public databases of pathogenic variations, we identified 143 reported pathogenic variants in 2KJPN for the 57 ACMG recommended genes based on a classification system. At the individual level, 21% of the individuals were found to have at least one reported pathogenic allele. We then conducted a literature survey to review the variants and to check for evidence of pathogenicity. Our results suggest that a substantial number of people have reported pathogenic alleles for the ACMG genes, and reviewing variants is indispensable for constructing the information infrastructure of genomic medicine for the Japanese population.

    DOI: 10.1038/s10038-017-0347-1

  • Identification of somatic genetic alterations in ovarian clear cell carcinoma with next generation sequencing 査読

    Yusuke Shibuya, Hideki Tokunaga, Sakae Saito, Kazurou Shimokawa, Fumiki Katsuoka, Li Bin, Kaname Kojima, Masao Nagasaki, Masayuki Yamamoto, Nobuo Yaegashi, Jun Yasuda

    GENES CHROMOSOMES & CANCER   57 ( 2 )   51 - 60   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ovarian clear cell carcinoma (OCCC) is the most refractory subtype of ovarian cancer and more prevalent in Japanese than Caucasians (25% and 5% of all ovarian cancer, respectively). The aim of this study is to discover the genomic alterations that may cause OCCC and effective molecular targets for chemotherapy. Paired genomic DNAs of 48 OCCC tissues and corresponding noncancerous tissues were extracted from formalin-fixed, paraffin embedded specimens collected between 2007 and 2015 at Tohoku University Hospital. All specimens underwent exome sequencing and the somatic genetic alterations were identified. We divided the cases into three clusters based on the mutation spectra. Clinical characteristics such as age of onset and endometriosis are similar among the clusters but one cluster shows mutations related to APOBEC activation, indicating its contribution to subset of OCCC cases. There are three hypermutated cases (showing 12-fold or higher somatic mutations than the other 45 cases) and they have germline and somatic mismatch repair gene alterations. The frequently mutated genes are ARID1A (66.7%), PIK3CA (50%), PPP2R1A (18.8%), and KRAS (16.7%). Somatic mutations important for selection of chemotherapeutic agents, such as BRAF, ERBB2, PDGFRB, PGR, and KRAS are found in 27.1% of OCCC cases, indicating clinical importance of exome analysis for OCCC. Our study suggests that the genetic instability caused by either mismatch repair defect or activation of APOBEC play critical roles in OCCC carcinogenesis.

    DOI: 10.1002/gcc.22507

  • Genetic analysis of Japanese primary open-angle glaucoma patients and clinical characterization of risk alleles near CDKN2B-AS1, SIX6 and GAS7 査読

    Yukihiro Shiga, Japan Glaucoma Society Omics Group (JGS-OG), Koji M. Nishiguchi, Yosuke Kawai, Kaname Kojima, Kota Sato, Kosuke Fujita, Mai Takahashi, Kazuko Omodaka, Makoto Araie, Kenji Kashiwagi, Makoto Aihara, Takeshi Iwata, Fumihiko Mabuchi, Mitsuko Takamoto, Mineo Ozaki, Kazuhide Kawase, Nobuo Fuse, Masayuki Yamamoto, Jun Yasuda, Masao Nagasaki, Toru Nakazawa

    PLoS ONE   12 ( 12 )   e0186678 - e0186678   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Purpose To test the genetic association between Japanese patients with primary open-angle glaucoma (POAG) and the previously reported POAG susceptibility loci and to perform genotype–phenotype analysis. Methods Genetic associations for 27 SNPs from 16 loci previously linked to POAG were assessed using genome-wide SNP data of the primary cohort (565 Japanese POAG patients and 1,104 controls). Reproducibility of the assessment was tested in 607 POAG cases and 455 controls (second cohort) with a targeted genotyping approach. For POAG-associated variants, a genotype–phenotype correlation study (additive, dominant, recessive model) was performed using the objective clinical data derived from 598 eyes of 598 POAG patients. Results Among 27 SNPs from 16 loci previously linked to POAG, genotypes for total of 20 SNPs in 13 loci were available for targeted association study. Among 8 SNPs in 3 loci that showed at least nominal association (P &lt
    5.00E-02) in the primary cohort, a representative SNP for each loci (rs2157719 for CDKN2B-AS1, rs33912345 for SIX6, and rs9913911 for GAS7) were selected. For these SNPs the association was found significant in both the second cohort analysis and meta-analysis. The genotype–phenotype analysis revealed significant correlations between CDKN2B-AS1 (rs2157719) and decreased intraocular pressure (? = -6.89 mmHg, P = 1.70E-04
    dominant model) after multiple corrections. In addition, nominal correlation was observed between CDKN2B-AS1 (rs2157719) and optic nerve head blood flow (? = -0.54 and -0.67 arbitrary units (AU), P = 2.00E-02 and 1.39E-02), between SIX6 (rs33912345) and decreased total peripapillary retinal nerve fiber layer thickness (? = -2.16 and -2.82 ?m, P = 4.68E-02 and 2.40E-02, additive and recessive model, respectively) and increased optic nerve head blood flow (? = 0.44 AU, P = 2.20E-02
    additive model) and between GAS7 (rs9913911) and increased cup volume (? = 0.03 mm3, P = 4.60E-02) and mean cup depth (? = 0.03 mm3, P = 4.11E-02
    additive model) and decreased pattern standard deviation (? = -0.87 dB, P = 2.44E-02
    dominant model). Conclusion The association between SNPs near GAS7 and POAG was found in Japanese patients for the first time. Clinical characterization of the risk variants is an important step toward understanding the pathology of the disease and optimizing treatment of patients with POAG.

    DOI: 10.1371/journal.pone.0186678

  • Security controls in an integrated Biobank to protect privacy in data sharing: rationale and study design 査読

    Takako Takai-Igarashi, Kengo Kinoshita, Masao Nagasaki, Soichi Ogishima, Naoki Nakamura, Sachiko Nagase, Satoshi Nagaie, Tomo Saito, Fuji Nagami, Naoko Minegishi, Yoichi Suzuki, Kichiya Suzuki, Hiroaki Hashizume, Shinichi Kuriyama, Atsushi Hozawa, Nobuo Yaegashi, Shigeo Kure, Gen Tamiya, Yoshio Kawaguchi, Hiroshi Tanaka, Masayuki Yamamoto

    BMC MEDICAL INFORMATICS AND DECISION MAKING   17 ( 1 )   100 - 100   2017年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: With the goal of realizing genome-based personalized healthcare, we have developed a biobank that integrates personal health, genome, and omics data along with biospecimens donated by volunteers of 150,000. Such a large-scale of data integration involves obvious risks of privacy violation. The research use of personal genome and health information is a topic of global discussion with regard to the protection of privacy while promoting scientific advancement. The present paper reports on our plans, current attempts, and accomplishments in addressing security problems involved in data sharing to ensure donor privacy while promoting scientific advancement.
    Methods: Biospecimens and data have been collected in prospective cohort studies with the comprehensive agreement. The sample size of 150,000 participants was required for multiple researches including genome-wide screening of gene by environment interactions, haplotype phasing, and parametric linkage analysis.
    Results: We established the Tohoku Medical Megabank (TMM) data sharing policy: a privacy protection rule that requires physical, personnel, and technological safeguards against privacy violation regarding the use and sharing of data. The proposed policy refers to that of NCBI and that of the Sanger Institute. The proposed policy classifies shared data according to the strength of re-identification risks. Local committees organized by TMM evaluate re-identification risk and assign a security category to a dataset. Every dataset is stored in an assigned segment of a supercomputer in accordance with its security category. A security manager should be designated to handle all security problems at individual data use locations. The proposed policy requires closed networks and IP-VPN remote connections.
    Conclusion: The mission of the biobank is to distribute biological resources most productively. This mission motivated us to collect biospecimens and health data and simultaneously analyze genome/omics data in-house. The biobank also has the mission of improving the quality and quantity of the contents of the biobank. This motivated us to request users to share the results of their research as feedback to the biobank. The TMM data sharing policy has tackled every security problem originating with the missions. We believe our current implementation to be the best way to protect privacy in data sharing.

    DOI: 10.1186/s12911-017-0494-5

  • Analysis of Müller glia specific genes and their histone modification using Hes1-promoter driven EGFP expressing mouse. 査読

    Ueno K, Iwagawa T, Ochiai G, Koso H, Nakauchi H, Nagasaki M, Suzuki Y, Watanabe S

    Scientific reports   7 ( 1 )   3578 - 3578   2017年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Analysis of Muller glia specific genes and their histone modification using Hes1-promoter driven EGFP expressing mouse
    Retinal neurons and Muller glia are generated from a common population of multipotent retinal progenitor cells. We purposed to identify Muller glia-specific molecular signatures during retinal development. Using transgenic mice carrying the Hes1 promoter (pHes1) followed by EGFP, we purified EGFP-positive Muller glia and other EGFP-negative retinal cells from developing retinas and subjected them to RNA sequencing analysis. Gene expression pattern of EGFP-positive cell was similar to genes expressed in retinal progenitors, and they were downregulated in other cell lineages. Then, we examined the modification profiles of H3K27me3 and H3K4me3 by referring to chromatin immunoprecipitation-sequencing data of rods and other cells. Clustering of the H3K4me3 and H3K27me3 values followed by ontology analysis revealed a high incidence of transcription factors including Hes1 in clusters with high H3K27me3 levels. Hes1 expression level decreased dramatically, and the H3K27me3 level at the Hes1-locus was upregulated strongly during retinal development. Furthermore, the Hes1 expression level was upregulated in an Ezh2-knockout retina. These results suggest that downregulation of Muller glia-related genes in other lineage rather than upregulation of them in Muller glia contributed Muller-specific molecular features, and a role for modified H3K27me3 in suppressing Muller glia-related genes in other retinal cell lineages to avoid unfavorable expression.

    DOI: 10.1038/s41598-017-03874-8

  • Identification of the functional variant driving ORMDL3 and GSDMB expression in human chromosome 17q12-21 in primary biliary cholangitis 査読

    Yuki Hitomi, Kaname Kojima, Minae Kawashima, Yosuke Kawai, Nao Nishida, Yoshihiro Aiba, Michio Yasunami, Masao Nagasaki, Minoru Nakamura, Katsushi Tokunaga

    SCIENTIFIC REPORTS   7 ( 1 )   2904 - 2904   2017年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Numerous genome-wide association studies (GWAS) have been performed to identify susceptibility genes to various human complex diseases. However, in many cases, neither a functional variant nor a disease susceptibility gene have been clarified. Here, we show an efficient approach for identification of a functional variant in a primary biliary cholangitis (PBC)-susceptible region, chromosome 17q12-21 (ORMDL3-GSDMB-ZPBP2-IKZF3). High-density association mapping was carried out based on SNP imputation analysis by using the whole-genome sequence data from a reference panel of 1,070 Japanese individuals (1KJPN), together with genotype data from our previous GWAS (PBC patients: n = 1,389; healthy controls: n = 1,508). Among 23 single nucleotide polymorphisms (SNPs) with P < 1.0 x 10(-8), rs12946510 was identified as the functional variant that influences gene expression via alteration of Forkhead box protein O1 (FOXO1) binding affinity in vitro. Moreover, expression-quantitative trait locus (e-QTL) analyses showed that the PBC susceptibility allele of rs12946510 was significantly associated with lower endogenous expression of ORMDL3 and GSDMB in whole blood and spleen. This study not only identified the functional variant in chr. 17q12-21 and its molecular mechanism through which it conferred susceptibility to PBC, but it also illustrated an efficient systematic approach for post-GWAS analysis that is applicable to other complex diseases.

    DOI: 10.1038/s41598-017-03067-3

  • A Histologic Categorization of Aqueous Outflow Routes in Familial Open-Angle Glaucoma and Associations With Mutations in the MYOC Gene in Japanese Patients 査読

    Teruhiko Hamanaka, Masae Kimura, Tetsuro Sakurai, Nobuo Ishida, Jun Yasuda, Masao Nagasaki, Naoki Nariai, Atsushi Endo, Kei Homma, Fumiki Katsuoka, Yoichi Matsubara, Masayuki Yamamoto, Nobuo Fuse

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE   58 ( 5 )   2818 - 2831   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE. This study evaluated specific relationships between pathogenic mechanisms and genetic polymorphisms in primary open-angle glaucoma (POAG). We analyzed the morphologies of trabeculectomy specimens obtained from patients with familial POAG.
    METHODS. We used light microscopy and transmission electron microscopy to examine specimens obtained from 17 eyes of 14 patients with familial POAG. We also conducted exome analyses of two families and used targeted Sanger sequencing to analyze samples obtained from the remaining patients.
    RESULTS. The POAG cases examined in this study were divided into two groups based on morphologic characteristics. Group A eyes (7 eyes from 5 patients) had an abnormally thick trabecular meshwork (TM), whereas group B eyes (10 eyes from 9 patients) had a TM of normal thickness. The characteristics of the outflow routes in group A eyes were remarkable and included apoptotic TM cells, abnormally thickened TM basement membranes, fused TM beams, and occluded Schlemm's canals. All group A patients harbored mutations (F369L, P370L, T377M, and T448P) in the myocilin (MYOC) gene that were not found in group B patients.
    CONCLUSIONS. Although age matching of morphologic changes in the outflow routes was impossible due to the small sample size, this study suggests that abnormal TM cells may cause sequential damage in abnormally thickened TM basement membranes, TM cell apoptosis, TM beam fusion, and the occlusion of Schlemm's canals. The four detected MYOC mutations appeared to be associated with morphologic changes in the TM and the underlying pathogenesis of a subtype of familial POAG.

    DOI: 10.1167/iovs.16-20646

  • Genome-Wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection 査読

    Kentaro Matsuura, Hiromi Sawai, Kazuho Ikeo, Shintaro Ogawa, Etsuko Iio, Masanori Isogawa, Noritomo Shimada, Atsumasa Komori, Hidenori Toyoda, Takashi Kumada, Tadashi Namisaki, Hitoshi Yoshiji, Naoya Sakamoto, Mina Nakagawa, Yasuhiro Asahina, Masayuki Kurosaki, Namiki Izumi, Nobuyuki Enomoto, Atsunori Kusakabe, Eiji Kajiwara, Yoshito Itoh, Tatsuya Ide, Akihiro Tamori, Misako Matsubara, Norifumi Kawada, Ken Shirabe, Eiichi Tomita, Masao Honda, Shuichi Kaneko, Sohji Nishina, Atsushi Suetsugu, Yoichi Hiasa, Hisayoshi Watanabe, Takuya Genda, Isao Sakaida, Shuhei Nishiguchi, Koichi Takaguchi, Eiji Tanaka, Junichi Sugihara, Mitsuo Shimada, Yasuteru Kondo, Yosuke Kawai, Kaname Kojima, Masao Nagasaki, Katsushi Tokunaga, Yasuhito Tanaka

    GASTROENTEROLOGY   152 ( 6 )   1383 - 1394   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND & AIMS: There is still a risk for hepatocellular carcinoma (HCC) development after eradication of hepatitis C virus (HCV) infection with antiviral agents. We investigated genetic factors associated with the development of HCC in patients with a sustained virologic response (SVR) to treatment for chronic HCV infection. METHODS: We obtained genomic DNA from 457 patients in Japan with a SVR to interferon-based treatment for chronic HCV infection from 2007 through 2015. We conducted a genome-wide association study (GWAS), followed by a replication analysis of 79 candidate single nucleotide polymorphisms (SNPs) in an independent set of 486 patients in Japan. The study end point was HCC diagnosis or confirmation of lack of HCC (at follow-up examinations until December 2014 in the GWAS cohort, and until January 2016 in the replication cohort). We collected clinical and laboratory data from all patients. We analyzed expression levels of candidate gene variants in human hepatic stellate cells, rats with steatohepatitis caused by a choline-deficient L-amino acid-defined diet, and a mouse model of liver injury caused by administration of carbon tetrachloride. We also analyzed expression levels in liver tissues of patients with chronic HCV infection with different stages of fibrosis or tumors vs patients without HCV infection (controls). RESULTS: We found a strong association between the SNP rs17047200, located within the intron of the tolloid like 1 gene (TLL1) on chromosome 4, and development of HCC; there was a genome-wide level of significance when the results of the GWAS and replication study were combined (odds ratio, 2.37; P = 2.66 x 10(-8)). Multivariate analysis showed rs17047200 AT/TT to be an independent risk factor for HCC (hazard ratio, 1.78; P = .008), along with male sex, older age, lower level of albumin, advanced stage of hepatic fibrosis, presence of diabetes, and higher post-treatment level of alpha-fetoprotein. Combining the rs17047200 genotype with other factors, we developed prediction models for HCC development in patients with mild or advanced hepatic fibrosis. Levels of TLL1 messenger RNA (mRNA) in human hepatic stellate cells increased with activation. Levels of Tll1 mRNA increased in liver tissues of rodents with hepatic fibrogenesis compared with controls. Levels of TLL1 mRNA increased in liver tissues of patients with progression of fibrosis. Gene expression levels of TLL1 short variants, including isoform 2, were higher in patients with rs17047200 AT/TT. CONCLUSIONS: In a GWAS, we identified the association between the SNP rs17047200, within the intron of TLL1, and development of HCC in patients who achieved an SVR to treatment for chronic HCV infection. We found levels of Tll1/TLL1 mRNA to be increased in rodent models of liver injury and liver tissues of patients with fibrosis, compared with controls. We propose that this SNP might affect splicing of TLL1 mRNA, yielding short variants with high catalytic activity that accelerates hepatic fibrogenesis and carcinogenesis. Further studies are needed to determine how rs17047200 affects TLL1 mRNA levels, splicing, and translation, as well as the prevalence of this variant among other patients with HCC. Tests for the TLL1 SNP might be used to identify patients at risk for HCC after an SVR to treatment of HCV infection.

    DOI: 10.1053/j.gastro.2017.01.041

  • Genome-wide association study using the ethnicity-specific Japonica array: identification of new susceptibility loci for cold medicine-related Stevens-Johnson syndrome with severe ocular complications 査読

    Mayumi Ueta, Hiromi Sawai, Ryosei Shingaki, Yusuke Kawai, Chie Sotozono, Kaname Kojima, Kyung-Chul Yoon, Mee Kum Kim, Kyoung Yul Seo, Choun-Ki Joo, Masao Nagasaki, Shigeru Kinoshita, Katsushi Tokunaga

    JOURNAL OF HUMAN GENETICS   62 ( 4 )   485 - 489   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A genome-wide association study (GWAS) for cold medicine-related Stevens-Johnson syndrome (CM-SJS) with severe ocular complications (SOC) was performed in a Japanese population. A recently developed ethnicity-specific array with genome-wide imputation that was based on the whole-genome sequences of 1070 unrelated Japanese individuals was used. Validation analysis with additional samples from Japanese individuals and replication analysis using samples from Korean individuals identified two new susceptibility loci on chromosomes 15 and 16. This study might suggest the usefulness of GWAS using the ethnicity-specific array and genome-wide imputation based on large-scale whole-genome sequences. Our findings contribute to the understanding of genetic predisposition to CM-SJS with SOC.

    DOI: 10.1038/jhg.2016.160

  • Genome-wide identification of inter-individually variable DNA methylation sites improves the efficacy of epigenetic association studies 査読

    Tsuyoshi Hachiya, Ryohei Furukawa, Yuh Shiwa, Hideki Ohmomo, Kanako Ono, Fumiki Katsuoka, Masao Nagasaki, Jun Yasuda, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto, Kozo Tanno, Mamoru Satoh, Ryujin Endo, Makoto Sasaki, Kiyomi Sakata, Seiichiro Kobayashi, Kuniaki Ogasawara, Jiro Hitomi, Kenji Sobue, Atsushi Shimizu

    NPJ GENOMIC MEDICINE   2   11 - 11   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Epigenome-wide association studies, which searches for blood-based DNA methylation signatures associated with environmental exposures and/or disease susceptibilities, is a promising approach to a better understanding of the molecular aetiology of common diseases. To carry out large-scale epigenome-wide association studies while avoiding false negative detection, an efficient strategy to determine target CpG sites for microarray-based or sequencing-based DNA methylation profiling is essentially needed. Here, we propose and validate a hypothesis that a strategy focusing on CpG sites with high DNA methylation level variability may attain an improved efficacy. Through whole-genome bisulfite sequencing of purified blood cells collected from > 100 apparently healthy subjects, we identified similar to 2.0 million inter-individually variable CpG sites as potential targets. The efficacy of our strategy was estimated to be 3.7-fold higher than that of the most frequently used strategy. Our catalogue of inter-individually variable CpG sites will accelerate the discovery of clinically relevant DNA methylation biomarkers in future epigenome-wide association studies.

    DOI: 10.1038/s41525-017-0016-5

  • LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn's disease patients. 査読 国際誌

    Liu TC, Naito T, Liu Z, VanDussen KL, Haritunians T, Li D, Endo K, Kawai Y, Nagasaki M, Kinouchi Y, McGovern DP, Shimosegawa T, Kakuta Y, Stappenbeck TS

    JCI insight   2 ( 6 )   e91917 - e91917   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn's disease patients.
    BACKGROUND. Morphological patterns of Paneth cells are a prognostic biomarker in Western Crohn's disease (CD) patients, and are associated with autophagy-associated ATG16L1 and NOD2 variants. We hypothesized that genetic determinants of Paneth cell phenotype in other ethnic CD cohorts are distinct but also involved in autophagy. METHODS. We performed a hypothesis-driven analysis of 56 single nucleotide polymorphisms (SNPs) associated with CD susceptibility or known to affect Paneth cell function in 110 Japanese CD patients who underwent ileal resection. We subsequently performed a genome-wide association analysis. Paneth cell phenotype was determined by defensin-5 immunofluorescence. Selected genotype-Paneth cell defect correlations were compared to a Western CD cohort (n = 164). RESULTS. The average percentage of abnormal Paneth cells in Japanese CD was similar to Western CD (P = 0.87), and abnormal Paneth cell phenotype was also associated with early recurrence (P = 0.013). In contrast to Western CD, ATG16L1 T300A was not associated with Paneth cell defect in Japanese CD (P = 0.20). Among the 56 selected SNPs, only LRRK2 M2397T showed significant association with Paneth cell defect (P = 3.62 × 10-4), whereas in the Western CD cohort it was not (P = 0.76). Pathway analysis of LRRK2 and other candidate genes with P less than 5 × 10-4 showed connections with known CD susceptibility genes and links to autophagy and TNF-α networks. CONCLUSIONS. We found dichotomous effects of ATG16L1 and LRRK2 on Paneth cell defect between Japanese and Western CD. Genes affecting Paneth cell phenotype in Japanese CD were also associated with autophagy. Paneth cell phenotype also predicted prognosis in Japanese CD. FUNDING. Helmsley Charitable Trust, Doris Duke Foundation (grant 2014103), Japan Society for the Promotion of Science (KAKENHI grants JP15H04805 and JP15K15284), Crohn's and Colitis Foundation grant 274415, NIH (grants 1R56DK095820, K01DK109081, and UL1 TR000448).

    DOI: 10.1172/jci.insight.91917

  • Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population 査読

    Minae Kawashima, Yuki Hitomi, Yoshihiro Aiba, Nao Nishida, Kaname Kojima, Yosuke Kawai, Hitomi Nakamura, Atsushi Tanaka, Mikio Zeniya, Etsuko Hashimoto, Hiromasa Ohira, Kazuhide Yamamoto, Masanori Abe, Kazuhiko Nakao, Satoshi Yamagiwa, Shuichi Kaneko, Masao Honda, Takeji Umemura, Takafumi Ichida, Masataka Seike, Shotaro Sakisaka, Masaru Harada, Osamu Yokosuka, Yoshiyuki Ueno, Michio Senju, Tatsuo Kanda, Hidetaka Shibata, Takashi Himoto, Kazumoto Murata, Yasuhiro Miyake, Hirotoshi Ebinuma, Makiko Taniai, Satoru Joshita, Toshiki Nikami, Hajime Ota, Hiroshi Kouno, Hirotaka Kouno, Makoto Nakamuta, Nobuyoshi Fukushima, Motoyuki Kohjima, Tatsuji Komatsu, Toshiki Komeda, Yukio Ohara, Toyokichi Muro, Tsutomu Yamashita, Kaname Yoshizawa, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Kazuhiro Sugi, Keisuke Ario, Eiichi Takesaki, Atsushi Naganuma, Hiroshi Mano, Haruhiro Yamashita, Kouki Matsushita, Kazuhiko Yamauchi, Fujio Makita, Hideo Nishimura, Kiyoshi Furuta, Naohiro Takahashi, Masahiro Kikuchi, Naohiko Masaki, Tomohiro Tanaka, Sumito Tamura, Akira Mori, Shintaro Yagi, Ken Shirabe, Atsumasa Komori, Kiyoshi Migita, Masahiro Ito, Shinya Nagaoka, Seigo Abiru, Hiroshi Yatsuhashi, Michio Yasunami, Shinji Shimoda, Kenichi Harada, Hiroto Egawa, Yoshihiko Maehara, Shinji Uemoto, Norihiro Kokudo, Hajime Takikawa, Hiromi Ishibashi, Kazuaki Chayama, Masashi Mizokami, Masao Nagasaki, Katsushi Tokunaga, Minoru Nakamura

    HUMAN MOLECULAR GENETICS   26 ( 3 )   650 - 659   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A previous genome- wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC. In this study, we performed GWAS in additional 1,923 Japanese individuals (894 PBC cases and 1,029 healthy controls),and combined the results with the previous data. This GWAS, together with a subsequent replication study in an independent set of 7,024 Japanese individuals (512 PBC cases and 6,512 healthy controls), identified PRKCB (rs7404928) as a novel susceptibility locus for PBC ( odds ratio [OR] = 1.26, P = 4.13 x 10(-9)). Furthermore, a primary functional variant of PRKCB (rs35015313) was identified by genotype imputation using a phased panel of 1,070 Japanese individuals from a prospective, general population cohort study and subsequent in vitro functional analyses. These results may lead to improved understanding of the disease pathways involved in PBC, forming a basis for prevention of PBC and development of novel therapeutics.

    DOI: 10.1093/hmg/ddw406

  • Monitoring of minimal residual disease in early T-cell precursor acute lymphoblastic leukaemia by next-generation sequencing 査読

    Xiaoqing Pan, Naoki Nariai, Noriko Fukuhara, Sakae Saito, Yukuto Sato, Fumiki Katsuoka, Kaname Kojima, Yoko Kuroki, Inaho Danjoh, Rumiko Saito, Shin Hasegawa, Yoko Okitsu, Aiko Kondo, Yasushi Onishi, Fuji Nagami, Hideyasu Kiyomoto, Atsushi Hozawa, Nobuo Fuse, Masao Nagasaki, Ritsuko Shimizu, Jun Yasuda, Hideo Harigae, Masayuki Yamamoto

    BRITISH JOURNAL OF HAEMATOLOGY   176 ( 2 )   318 - 321   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/bjh.13948

  • STR-realigner: a realignment method for short tandem repeat regions. 査読

    Kojima K, Kawai Y, Misawa K, Mimori T, Nagasaki M

    BMC genomics   17 ( 1 )   991 - 991   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/s12864-016-3294-x

  • Conditional Rod Photoreceptor Ablation Reveals Sall1 as a Microglial Marker and Regulator of Microglial Morphology in the Retina 査読

    Hideto Koso, Asano Tsuhako, Chen-Yi Lai, Yukihiro Baba, Makoto Otsu, Kazuko Ueno, Masao Nagasaki, Yutaka Suzuki, Sumiko Watanabe

    GLIA   64 ( 11 )   2005 - 2024   2016年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neurodegeneration has been shown to induce microglial activation and the infiltration of monocyte-derived macrophages into the CNS, resulting in the coexistence of these two populations within the same lesion, though their distinct features remain elusive. To investigate the impact of rod photoreceptor degeneration on microglial activation, we generated a toxin-mediated genetic model of rod degeneration. Rod injury induced microglial proliferation and migration toward the photoreceptors. Bone marrow transplantation revealed the invasion of monocyte-derived macrophages into the retina, with microglia and the infiltrating macrophages showing distinct distribution patterns in the retina. By comparing the gene expression profiles of the activated microglia and infiltrating macrophages, we identified microglia-specific genes, including Ak1, Ctsf, Sall1, Phlda3, and Spns2. An analysis of Sall1gfp knock-in mice showed GFP expression in the microglia of developing and mature healthy retinas. DTA injury induced the expansion of Sall1gfp 1 microglia, whereas Ly6C(+) monocyte-derived macrophages were mostly Sall1gfp(-), supporting the idea that Sall1 is exclusively expressed in microglia within the retinal phagocyte pool. We evaluated the contribution of microglia to the phagocyte pool in rd1 mutant retinas and found that Sall1gfp 1 microglia constituted the majority of phagocytes. A Sall1 deficiency did not affect microglial colonization of the retina and the cortex, but it did change their morphology from a ramified to a more amoeboid appearance. The morphological defects observed in Sall1-deficient microglia were not rescued by the presence of wild-type non-microglial cells, suggesting that Sall1 functions cell-autonomously in microglia. Taken together, our data indicate that Sall1 regulates microglial morphology during development.

    DOI: 10.1002/glia.23038

  • The Tohoku Medical Megabank Project: Design and Mission 査読

    Shinichi Kuriyama, Nobuo Yaegashi, Fuji Nagami, Tomohiko Arai, Yoshio Kawaguchi, Noriko Osumi, Masaki Sakaida, Yoichi Suzuki, Keiko Nakayama, Hiroaki Hashizume, Gen Tamiya, Hiroshi Kawame, Kichiya Suzuki, Atsushi Hozawa, Naoki Nakaya, Masahiro Kikuya, Hirohito Metoki, Ichiro Tsuji, Nobuo Fuse, Hideyasu Kiyomoto, Junichi Sugawara, Akito Tsuboi, Shinichi Egawa, Kiyoshi Ito, Koichi Chida, Tadashi Ishii, Hiroaki Tomita, Yasuyuki Taki, Naoko Minegishi, Naoto Ishii, Jun Yasuda, Kazuhiko Igarashi, Ritsuko Shimizu, Masao Nagasaki, Seizo Koshiba, Kengo Kinoshita, Soichi Ogishima, Takako Takai-Igarashi, Teiji Tominaga, Osamu Tanabe, Noriaki Ohuchi, Toru Shimosegawa, Shigeo Kure, Hiroshi Tanaka, Sadayoshi Ito, Jiro Hitomi, Kozo Tanno, Motoyuki Nakamura, Kuniaki Ogasawara, Seiichiro Kobayashi, Kiyomi Sakata, Mamoru Satoh, Atsushi Shimizu, Makoto Sasaki, Ryujin Endo, Kenji Sobue, Masayuki Yamamoto

    JOURNAL OF EPIDEMIOLOGY   26 ( 9 )   493 - 511   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The Great East Japan Earthquake (GEJE) and resulting tsunami of March 11, 2011 gave rise to devastating damage on the Pacific coast of the Tohoku region. The Tohoku Medical Megabank Project (TMM), which is being conducted by Tohoku University Tohoku Medical Megabank Organization (ToMMo) and Iwate Medical University Iwate Tohoku Medical Megabank Organization (IMM), has been launched to realize creative reconstruction and to solve medical problems in the aftermath of this disaster. We started two prospective cohort studies in Miyagi and Iwate Prefectures: a population-based adult cohort study, the TMM Community-Based Cohort Study (TMM CommCohort Study), which will recruit 80 000 participants, and a birth and three-generation cohort study, the TMM Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study), which will recruit 70 000 participants, including fetuses and their parents, siblings, grandparents, and extended family members. The TMM CommCohort Study will recruit participants from 2013 to 2016 and follow them for at least 5 years. The TMM BirThree Cohort Study will recruit participants from 2013 to 2017 and follow them for at least 4 years. For children, the ToMMo Child Health Study, which adopted a cross-sectional design, was also started in November 2012 in Miyagi Prefecture. An integrated biobank will be constructed based on the two prospective cohort studies, and ToMMo and IMM will investigate the chronic medical impacts of the GEJE. The integrated biobank of TMM consists of health and clinical information, biospecimens, and genome and omics data. The biobank aims to establish a firm basis for personalized healthcare and medicine, mainly for diseases aggravated by the GEJE in the two prefectures. Biospecimens and related information in the biobank will be distributed to the research community. TMM itself will also undertake genomic and omics research. The aims of the genomic studies are: 1) to construct an integrated biobank; 2) to return genomic research results to the participants of the cohort studies, which will lead to the implementation of personalized healthcare and medicine in the affected areas in the near future; and 3) to contribute the development of personalized healthcare and medicine worldwide. Through the activities of TMM, we will clarify how to approach prolonged healthcare problems in areas damaged by large-scale disasters and how useful genomic information is for disease prevention.

    DOI: 10.2188/jea.JE20150268

  • AP-SKAT: highly-efficient genome-wide rare variant association test. 査読

    Hasegawa T, Kojima K, Kawai Y, Misawa K, Mimori T, Nagasaki M

    BMC genomics   17 ( 1 )   745 - 745   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/s12864-016-3094-3

  • 妊娠関連疾患の予防・早期発見のためのヘルスケアデータと多層オミックスデータの統合解析を目指して

    原田 祐希, 越智 大介, 山内 隆史, 山下 理宇, 檜山 聡, 長崎 正朗, 菅原 準一, マタニティログプロジェクトチーム

    日本生化学会大会プログラム・講演要旨集   89回   [3P - 253]   2016年9月

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    記述言語:日本語  

  • Variants in the UBR1 gene are not associated with chronic pancreatitis in Japan 査読

    Atsushi Masamune, Eriko Nakano, Tetsuya Niihori, Shin Hamada, Masao Nagasaki, Yoko Aoki, Tooru Shimosegawa

    PANCREATOLOGY   16 ( 5 )   814 - 818   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background/objectives: The UBR1 gene encodes the enzyme ubiquitin-protein ligase E3 component nrecognin 1. Loss-of-function mutations in the UBR1 gene cause Johanson-Blizzard syndrome, which involves pancreatic exocrine insufficiency. No previous studies have examined an association of UBR1 variants with pancreatitis, in part due to the large size of the gene. This study aimed to clarify whether UBR1 variants are associated with chronic pancreatitis (CP) by the application of targeted next generation sequencing.
    Methods: Exon sequences of the UBR1 gene from 389 Japanese patients with CP (188 idiopathic, 172 alcoholic, 20 hereditary, 9 familial) were captured by the HaloPlex target enrichment technology and subjected to next generation sequencing.
    Results: Ninety nine point two % of the coding regions of the UBR1 gene could be sequenced by >= 20 reads with a mean read depth of 595 and a median depth of 399. Fifteen non-synonymous variants including three novel ones [cA514T > C (p.11505T), c.4828C > G (p.H1610D) and c.4856A > T (p.D1619V)] and two synonymous variants were identified in the exonic regions. The frequency of any non synonymous or synonymous variants was not different between the patients with CP and controls.
    Conclusions: Variants in the UBR1 gene were not associated with CP in Japan. (C) 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.pan.2016.06.662

  • Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn's disease and leprosy 査読

    Yonghu Sun, Astrid Irwanto, Licht Toyo-oka, Myunghee Hong, Hong Liu, Anand Kumar Andiappan, Hyunchul Choi, Yuki Hitomi, Gongqi Yu, Yongxiang Yu, Fangfang Bao, Chuan Wang, Xian Fu, Zhenhua Yue, Honglei Wang, Huimin Zhang, Minae Kawashima, Kaname Kojima, Masao Nagasaki, Minoru Nakamura, Suk-Kyun Yang, Byong Duk Ye, Yosua Denise, Olaf Rotzschke, Kyuyoung Song, Katsushi Tokunaga, Furen Zhang, Jianjun Liu

    SCIENTIFIC REPORTS   6   31429 - 31429   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Genetic polymorphism within the 9q32 locus is linked with increased risk of several diseases, including Crohn's disease (CD), primary biliary cholangitis (PBC) and leprosy. The most likely disease-causing gene within 9q32 is TNFSF15, which encodes the pro-inflammatory cytokine TNF super-family member 15, but it was unknown whether these disparate diseases were associated with the same genetic variance in 9q32, and how variance within this locus might contribute to pathology. Using genetic data from published studies on CD, PBC and leprosy we revealed that bearing a T allele at rs6478108/ rs6478109 (r(2) = 1) or rs4979462 was significantly associated with increased risk of CD and decreased risk of leprosy, while the T allele at rs4979462 was associated with significantly increased risk of PBC. In vitro analyses showed that the rs6478109 genotype significantly affected TNFSF15 expression in cells from whole blood of controls, while functional annotation using publicly-available data revealed the broad cell type/tissue-specific regulatory potential of variance at rs6478109 or rs4979462. In summary, we provide evidence that variance within TNFSF15 has the potential to affect cytokine expression across a range of tissues and thereby contribute to protection from infectious diseases such as leprosy, while increasing the risk of immune-mediated diseases including CD and PBC.

    DOI: 10.1038/srep31429

  • The structural origin of metabolic quantitative diversity 査読

    Seizo Koshiba, Ikuko Motoike, Kaname Kojima, Takanori Hasegawa, Matsuyuki Shirota, Tomo Saito, Daisuke Saigusa, Inaho Danjoh, Fumiki Katsuoka, Soichi Ogishima, Yosuke Kawai, Yumi Yamaguchi-Kabata, Miyuki Sakurai, Sachiko Hirano, Junichi Nakata, Hozumi Motohashi, Atsushi Hozawa, Shinichi Kuriyama, Naoko Minegishi, Masao Nagasaki, Takako Takai-Igarashi, Nobuo Fuse, Hideyasu Kiyomoto, Junichi Sugawara, Yoichi Suzuki, Shigeo Kure, Nobuo Yaegashi, Osamu Tanabe, Kengo Kinoshita, Jun Yasuda, Masayuki Yamamoto

    SCIENTIFIC REPORTS   6   31463 - 31463   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Relationship between structural variants of enzymes and metabolic phenotypes in human population was investigated based on the association study of metabolite quantitative traits with whole genome sequence data for 512 individuals from a population cohort. We identified five significant associations between metabolites and non-synonymous variants. Four of these non-synonymous variants are located in enzymes involved in metabolic disorders, and structural analyses of these moderate non-synonymous variants demonstrate that they are located in peripheral regions of the catalytic sites or related regulatory domains. In contrast, two individuals with larger changes of metabolite levels were also identified, and these individuals retained rare variants, which caused non-synonymous variants located near the catalytic site. These results are the first demonstrations that variant frequency, structural location, and effect for phenotype correlate with each other in human population, and imply that metabolic individuality and susceptibility for diseases may be elicited from the moderate variants and much more deleterious but rare variants.

    DOI: 10.1038/srep31463

  • Short tandem repeat number estimation from paired-end reads for multiple individuals by considering coalescent tree 査読

    Kaname Kojima, Yosuke Kawai, Naoki Nariai, Takahiro Mimori, Takanori Hasegawa, Masao Nagasaki

    BMC GENOMICS   17   494 - 494   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Two types of approaches are mainly considered for the repeat number estimation in short tandem repeat (STR) regions from high-throughput sequencing data: approaches directly counting repeat patterns included in sequence reads spanning the region and approaches based on detecting the difference between the insert size inferred from aligned paired-end reads and the actual insert size. Although the accuracy of repeat numbers estimated with the former approaches is high, the size of target STR regions is limited to the length of sequence reads. On the other hand, the latter approaches can handle STR regions longer than the length of sequence reads. However, repeat numbers estimated with the latter approaches is less accurate than those with the former approaches.
    Results: We proposed a new statistical model named coalescentSTR that estimates repeat numbers from paired-end read distances for multiple individuals simultaneously by connecting the read generative model for each individual with their genealogy. In the model, the genealogy is represented by handling coalescent trees as hidden variables, and the summation of the hidden variables is taken on coalescent trees sampled based on phased genotypes located around a target STR region with Markov chain Monte Carlo. In the sampled coalescent trees, repeat number information from insert size data is propagated, and more accurate estimation of repeat numbers is expected for STR regions longer than the length of sequence reads. For finding the repeat numbers maximizing the likelihood of the model on the estimation of repeat numbers, we proposed a state-of-the-art belief propagation algorithm on sampled coalescent trees.
    Conclusions: We verified the effectiveness of the proposed approach from the comparison with existing methods by using simulation datasets and real whole genome and whole exome data for HapMap individuals analyzed in the 1000 Genomes Project.

    DOI: 10.1186/s12864-016-2821-0

  • Transition of differential histone H3 methylation in photoreceptors and other retinal cells during retinal differentiation 査読

    Kazuko Ueno, Toshiro Iwagawa, Hiroshi Kuribayashi, Yukihiro Baba, Hiromitsu Nakauchi, Akira Murakami, Masao Nagasaki, Yutaka Suzuki, Sumiko Watanabe

    SCIENTIFIC REPORTS   6   29264 - 29264   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To analyze cell lineage-specific transitions in global transcriptional and epigenetic changes during retinogenesis, we purified retinal cells from normal mice during postnatal development into two fractions, namely, photoreceptors and other retinal cells, based on Cd73 expression, and performed RNA sequencing and ChIP sequencing of H3K27me3 and H3K4me3. Genes expressed in the photoreceptor lineage were marked with H3K4me3 in the Cd73-positive cell fraction; however, the level of H3K27me3 was very low in both Cd73-positive and -negative populations. H3K27me3 may be involved in spatio-temporal onset of a subset of bipolar-related genes. Subsets of genes expressed in amacrine and retinal ganglion cells, which are early-born retinal cell types, were suggested to be maintained in a silent state by H3K27me3 during late-stage retinogenesis. In the outer nuclear layer, upregulation of Rho and rod-related genes were observed in Ezh2-ablated retina, suggesting a role for H3K27me3 in the maintenance of proper expression levels. Taken together, our data on the transition of lineage-specific molecular signatures during development suggest that histone methylation is involved in retinal differentiation and maintenance through cell lineage-specific mechanisms.

    DOI: 10.1038/srep29264

  • Comparison of Boiling and Robotics Automation Method in DNA Extraction for Metagenomic Sequencing of Human Oral Microbes 査読

    Junya Yamagishi, Yukuto Sato, Natsuko Shinozaki, Bin Ye, Akito Tsuboi, Masao Nagasaki, Riu Yamashita

    PLOS ONE   11 ( 4 )   e0154389 - e0154389   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The rapid improvement of next-generation sequencing performance now enables us to analyze huge sample sets with more than ten thousand specimens. However, DNA extraction can still be a limiting step in such metagenomic approaches. In this study, we analyzed human oral microbes to compare the performance of three DNA extraction methods: PowerSoil (a method widely used in this field), QIAsymphony (a robotics method), and a simple boiling method. Dental plaque was initially collected from three volunteers in the pilot study and then expanded to 12 volunteers in the follow-up study. Bacterial flora was estimated by sequencing the V4 region of 16S rRNA following species-level profiling. Our results indicate that the efficiency of PowerSoil and QIAsymphony was comparable to the boiling method. Therefore, the boiling method may be a promising alternative because of its simplicity, cost effectiveness, and short handling time. Moreover, this method was reliable for estimating bacterial species and could be used in the future to examine the correlation between oral flora and health status. Despite this, differences in the efficiency of DNA extraction for various bacterial species were observed among the three methods. Based on these findings, there is no "gold standard" for DNA extraction. In future, we suggest that the DNA extraction method should be selected on a case-by-case basis considering the aims and specimens of the study.

    DOI: 10.1371/journal.pone.0154389

  • A Bayesian approach for estimating allele-specific expression from RNA-Seq data with diploid genomes 査読

    Naoki Nariai, Kaname Kojima, Takahiro Mimori, Yosuke Kawai, Masao Nagasaki

    BMC GENOMICS   17   2 - 2   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: RNA-sequencing (RNA-Seq) has become a popular tool for transcriptome profiling in mammals. However, accurate estimation of allele-specific expression (ASE) based on alignments of reads to the reference genome is challenging, because it contains only one allele on a mosaic haploid genome. Even with the information of diploid genome sequences, precise alignment of reads to the correct allele is difficult because of the high-similarity between the corresponding allele sequences.
    Results: We propose a Bayesian approach to estimate ASE from RNA-Seq data with diploid genome sequences. In the statistical framework, the haploid choice is modeled as a hidden variable and estimated simultaneously with isoform expression levels by variational Bayesian inference. Through the simulation data analysis, we demonstrate the effectiveness of the proposed approach in terms of identifying ASE compared to the existing approach. We also show that our approach enables better quantification of isoform expression levels compared to the existing methods, TIGAR2, RSEM and Cufflinks. In the real data analysis of the human reference lymphoblastoid cell line GM12878, some autosomal genes were identified as ASE genes, and skewed paternal X-chromosome inactivation in GM12878 was identified.
    Conclusions: The proposed method, called ASE-TIGAR, enables accurate estimation of gene expression from RNA-Seq data in an allele-specific manner. Our results show the effectiveness of utilizing personal genomic information for accurate estimation of ASE. An implementation of our method is available at http://nagasakilab.csml.org/ase-tigar.

    DOI: 10.1186/s12864-015-2295-5

  • A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies 査読

    Masakazu Kohda, Yoshimi Tokuzawa, Yoshihito Kishita, Hiromi Nyuzuki, Yohsuke Moriyama, Yosuke Mizuno, Tomoko Hirata, Yukiko Yatsuka, Yzumi Yamashita-Sugahara, Yutaka Nakachi, Hidemasa Kato, Akihiko Okuda, Shunsuke Tamaru, Nurun Nahar Borna, Kengo Banshoya, Toshiro Aigaki, Yukiko Sato-Miyata, Kohei Ohnuma, Tsutomu Suzuki, Asuteka Nagao, Hazuki Maehata, Fumihiko Matsuda, Koichiro Higasa, Masao Nagasaki, Jun Yasuda, Masayuki Yamamoto, Takuya Fushimi, Masaru Shimura, Keiko Kaiho-Ichimoto, Hiroko Harashima, Taro Yamazaki, Masato Mori, Kei Murayama, Akira Ohtake, Yasushi Okazaki

    PLoS Genetics   12 ( 1 )   e1005679 - e1005679   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity. Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production and mitochondrial disorders. More than 250 genes that cause mitochondrial disorders have been reported to date. However exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed comprehensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration analyses using high-density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and 3 mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as novel causative genes. We also identified 2 genes known to cause monogenic diseases (MECP2 and TNNI3) and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21) as causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic heterogeneity and will improve patient care of this complex disorder.

    DOI: 10.1371/journal.pgen.1005679

  • Japonica array: improved genotype imputation by designing a population-specific SNP array with 1070 Japanese individuals 査読

    Yosuke Kawai, Takahiro Mimori, Kaname Kojima, Naoki Nariai, Inaho Danjoh, Rumiko Saito, Jun Yasuda, Masayuki Yamamoto, Masao Nagasaki

    JOURNAL OF HUMAN GENETICS   60 ( 10 )   581 - 587   2015年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The Tohoku Medical Megabank Organization constructed the reference panel (referred to as the 1KJPN panel), which contains 420 million single nucleotide polymorphisms (SNPs), from whole-genome sequence data from 1070 Japanese individuals. The 1KJPN panel contains the largest number of haplotypes of Japanese ancestry to date. Here, from the 1KJPN panel, we designed a novel custom-made SNP array, named the Japonica array, which is suitable for whole-genome imputation of Japanese individuals. The array contains 659 253 SNPs, including tag SNPs for imputation, SNPs of Y chromosome and mitochondria, and SNPs related to previously reported genome-wide association studies and pharmacogenomics. The Japonica array provides better imputation performance for Japanese individuals than the existing commercially available SNP arrays with both the 1KJPN panel and the International 1000 genomes project panel. For common SNPs (minor allele frequency (MAF) > 5%), the genomic coverage of the Japonica array (r(2)>0.8) was 96.9%, that is, almost all common SNPs were covered by this array. Nonetheless, the coverage of low-frequency SNPs (0.5% < MAF <= 5%) of the Japonica array reached 67.2%, which is higher than those of the existing arrays. In addition, we confirmed the high quality genotyping performance of the Japonica array using the 288 samples in 1KJPN; the average call rate 99.7% and the average concordance rate 99.7% to the genotypes obtained from high-throughput sequencer. As demonstrated in this study, the creation of custom-made SNP arrays based on a populationspecific reference panel is a practical way to facilitate further association studies through genome-wide genotype imputations.

    DOI: 10.1038/jhg.2015.68

  • Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals 査読

    Masao Nagasaki, Jun Yasuda, Fumiki Katsuoka, Naoki Nariai, Kaname Kojima, Yosuke Kawai, Yumi Yamaguchi-Kabata, Junji Yokozawa, Inaho Danjoh, Sakae Saito, Yukuto Sato, Takahiro Mimori, Kaoru Tsuda, Rumiko Saito, Xiaoqing Pan, Satoshi Nishikawa, Shin Ito, Yoko Kuroki, Osamu Tanabe, Nobuo Fuse, Shinichi Kuriyama, Hideyasu Kiyomoto, Atsushi Hozawa, Naoko Minegishi, James Douglas Engel, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto

    NATURE COMMUNICATIONS   6   8018 - 8018   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The Tohoku Medical Megabank Organization reports the whole-genome sequences of 1,070 healthy Japanese individuals and construction of a Japanese population reference panel (1KJPN). Here we identify through this high-coverage sequencing (32.4 x on average), 21.2 million, including 12 million novel, single-nucleotide variants (SNVs) at an estimated false discovery rate of <1.0%. This detailed analysis detected signatures for purifying selection on regulatory elements as well as coding regions. We also catalogue structural variants, including 3.4 million insertions and deletions, and 25,923 genic copy-number variants. The 1KJPN was effective for imputing genotypes of the Japanese population genome wide. These data demonstrate the value of high-coverage sequencing for constructing population-specific variant panels, which covers 99.0% SNVs of minor allele frequency >= 0.1%, and its value for identifying causal rare variants of complex human disease phenotypes in genetic association studies.

    DOI: 10.1038/ncomms9018

  • Short tandem repeat number estimation from paired-end sequence reads by considering unobserved genealogy of multiple individuals 査読

    Kaname Kojima, Yosuke Kawai, Naoki Nariai, Takahiro Mimori, Takanori Hasegawa, Masao Nagasaki

    Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)   9096   422 - 423   2015年8月

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    記述言語:英語   掲載種別:研究論文(その他学術会議資料等)  

    DOI: 10.1007/978-3-319-19048-8

  • Somatic alteration and depleted nuclear expression of BAP1 in human esophageal squamous cell carcinomas 査読

    Takahiro Mori, Makiko Sumii, Fumiyoshi Fujishima, Kazuko Ueno, Masao Nagasaki, Chikashi Ishioka, Natsuko Chiba

    CANCER RESEARCH   75   2015年8月

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    記述言語:英語  

    DOI: 10.1158/1538-7445.AM2015-4955

  • Inter-Individual Differences in the Oral Bacteriome Are Greater than Intra-Day Fluctuations in Individuals 査読

    Yukuto Sato, Junya Yamagishi, Riu Yamashita, Natsuko Shinozaki, Bin Ye, Takuji Yamada, Masayuki Yamamoto, Masao Nagasaki, Akito Tsuboi

    PLOS ONE   10 ( 6 )   e0131607 - e0131607   2015年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Given the advent of massively parallel DNA sequencing, human microbiome is analyzed comprehensively by metagenomic approaches. However, the inter-and intra-individual variability and stability of the human microbiome remain poorly characterized, particularly at the intra-day level. This issue is of crucial importance for studies examining the effects of microbiome on human health. Here, we focused on bacteriome of oral plaques, for which repeated, time-controlled sampling is feasible. Eighty-one supragingival plaque subjects were collected from healthy individuals, examining multiple sites within the mouth at three time points (forenoon, evening, and night) over the course of 3 days. Bacterial composition was estimated by 16S rRNA sequencing and species-level profiling, resulting in identification of a total of 162 known bacterial species. We found that species compositions and their relative abundances were similar within individuals, and not between sampling time or tooth type. This suggests that species-level oral bacterial composition differs significantly between individuals, although the number of subjects is limited and the intra-individual variation also occurs. The majority of detected bacterial species (98.2%; 159/162), however, did not fluctuate over the course of the day, implying a largely stable oral microbiome on an intra-day time scale. In fact, the stability of this data set enabled us to estimate potential interactions between rare bacteria, with 40 co-occurrences supported by the existing literature. In summary, the present study provides a valuable basis for studies of the human microbiome, with significant implications in terms of biological and clinical outcomes.

    DOI: 10.1371/journal.pone.0131607

  • Estimating copy numbers of alleles from population-scale high-throughput sequencing data 査読

    Takahiro Mimori, Naoki Nariai, Kaname Kojima, Yukuto Sato, Yosuke Kawai, Yumi Yamaguchi-Kabata, Masao Nagasaki

    BMC BIOINFORMATICS   16   S4 - S4   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: With the recent development of microarray and high-throughput sequencing (HTS) technologies, a number of studies have revealed catalogs of copy number variants (CNVs) and their association with phenotypes and complex traits. In parallel, a number of approaches to predict CNV regions and genotypes are proposed for both microarray and HTS data. However, only a few approaches focus on haplotyping of CNV loci.
    Results: We propose a novel approach to infer copy unit alleles and their numbers in each sample simultaneously from population-scale HTS data by variational Bayesian inference on a generative probabilistic model inspired by latent Dirichlet allocation, which is a well studied model for document classification problems. In simulation studies, we evaluated concordance between inferred and true copy unit alleles for lower-, middle-, and higher-copy number dataset, in which precision and recall were >= 0.9 for data with mean coverage >= 10x per copy unit. We also applied the approach to HTS data of 1123 samples at highly variable salivary amylase gene locus and a pseudogene locus, and confirmed consistency of the estimated alleles within samples belonging to a trio of CEPH/Utah pedigree 1463 with 11 offspring.
    Conclusions: Our proposed approach enables detailed analysis of copy number variations, such as association study between copy unit alleles and phenotypes or biological features including human diseases.

    DOI: 10.1186/1471-2105-16-S1-S4

  • HLA-VBSeq: accurate HLA typing at full resolution from whole-genome sequencing data 査読

    Naoki Nariai, Kaname Kojima, Sakae Saito, Takahiro Mimori, Yukuto Sato, Yosuke Kawai, Yumi Yamaguchi-Kabata, Jun Yasuda, Masao Nagasaki

    BMC GENOMICS   16   S7 - S7   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Human leucocyte antigen (HLA) genes play an important role in determining the outcome of organ transplantation and are linked to many human diseases. Because of the diversity and polymorphisms of HLA loci, HLA typing at high resolution is challenging even with whole-genome sequencing data.
    Results: We have developed a computational tool, HLA-VBSeq, to estimate the most probable HLA alleles at full (8-digit) resolution from whole-genome sequence data. HLA-VBSeq simultaneously optimizes read alignments to HLA allele sequences and abundance of reads on HLA alleles by variational Bayesian inference. We show the effectiveness of the proposed method over other methods through the analysis of predicting HLA types for HLA class I (HLA-A, -B and -C) and class II (HLA-DQA1,-DQB1 and -DRB1) loci from the simulation data of various depth of coverage, and real sequencing data of human trio samples.
    Conclusions: HLA-VBSeq is an efficient and accurate HLA typing method using high-throughput sequencing data without the need of primer design for HLA loci. Moreover, it does not assume any prior knowledge about HLA allele frequencies, and hence HLA-VBSeq is broadly applicable to human samples obtained from a genetically diverse population.

    DOI: 10.1186/1471-2164-16-S2-S7

  • An efficient quantitation method of next-generation sequencing libraries by using MiSeq sequencer 査読

    Fumiki Katsuoka, Junji Yokozawa, Kaoru Tsuda, Shin Ito, Xiaoqing Pan, Masao Nagasaki, Jun Yasuda, Masayuki Yamamoto

    ANALYTICAL BIOCHEMISTRY   466   27 - 29   2014年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Library quantitation is a critical step to obtain high data output in Illumina HiSeq sequencers. Here, we introduce a library quantitation method that uses the Illumina MiSeq sequencer designated as quantitative MiSeq (qMiSeq). In this procedure, 96 dual-index libraries, including control samples, are denatured, pooled in equal volume, and sequenced by MiSeq. We found that relative concentration of each library can be determined based on the observed index ratio and can be used to determine HiSeq run condition for each library. Thus, qMiSeq provides an efficient way to quantitate a large number of libraries at a time. (C) 2014 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.ab.2014.08.015

  • TIGAR2: sensitive and accurate estimation of transcript isoform expression with longer RNA-Seq reads 査読

    Naoki Nariai, Kaname Kojima, Takahiro Mimori, Yukuto Sato, Yosuke Kawai, Yumi Yamaguchi-Kabata, Masao Nagasaki

    BMC GENOMICS   15   S5 - S5   2014年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: High-throughput RNA sequencing (RNA-Seq) enables quantification and identification of transcripts at single-base resolution. Recently, longer sequence reads become available thanks to the development of new types of sequencing technologies as well as improvements in chemical reagents for the Next Generation Sequencers. Although several computational methods have been proposed for quantifying gene expression levels from RNA-Seq data, they are not sufficiently optimized for longer reads (e.g. > 250 bp).
    Results: We propose TIGAR2, a statistical method for quantifying transcript isoforms from fixed and variable length RNA-Seq data. Our method models substitution, deletion, and insertion errors of sequencers based on gapped-alignments of reads to the reference cDNA sequences so that sensitive read-aligners such as Bowtie2 and BWA-MEM are effectively incorporated in our pipeline. Also, a heuristic algorithm is implemented in variational Bayesian inference for faster computation. We apply TIGAR2 to both simulation data and real data of human samples and evaluate performance of transcript quantification with TIGAR2 in comparison to existing methods.
    Conclusions: TIGAR2 is a sensitive and accurate tool for quantifying transcript isoform abundances from RNA-Seq data. Our method performs better than existing methods for the fixed-length reads (100 bp, 250 bp, 500 bp, and 1000 bp of both single-end and paired-end) and variable-length reads, especially for reads longer than 250 bp.

    DOI: 10.1186/1471-2164-15-S10-S5

  • 胎生期ストレスが胎児のエピゲノム変化および精神行動に及ぼす影響の特定

    兪 志前, 舟山 亮, 植野 和子, 成相 直樹, 小島 要, 小野 千晶, 笠原 好之, 長崎 正朗, 中山 啓子, 富田 博秋

    日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集   24回・44回   204 - 204   2014年11月

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    記述言語:日本語  

  • Identification of acquired mutations by whole-genome sequencing in GATA-2 deficiency evolving into myelodysplasia and acute leukemia 査読

    Tohru Fujiwara, Noriko Fukuhara, Ryo Funayama, Naoki Nariai, Mayumi Kamata, Takeshi Nagashima, Kaname Kojima, Yasushi Onishi, Yoji Sasahara, Kenichi Ishizawa, Masao Nagasaki, Keiko Nakayama, Hideo Harigae

    ANNALS OF HEMATOLOGY   93 ( 9 )   1515 - 1522   2014年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Heterozygous GATA-2 germline mutations are associated with overlapping clinical manifestations termed GATA-2 deficiency, characterized by immunodeficiency and predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, there is considerable clinical heterogeneity among patients, and the molecular basis for the evolution of immunodeficiency into MDS/AML remains unknown. Thus, we conducted whole-genome sequencing on a patient with a germline GATA-2 heterozygous mutation (c. 988 C > T; p. R330X), who had a history suggestive of immunodeficiency and evolved into MDS/AML. Analysis was conducted with DNA samples from leukocytes for immunodeficiency, bone marrow mononuclear cells for MDS and bone marrow-derived mesenchymal stem cells. Whereas we did not identify a candidate genomic deletion that may contribute to the evolution into MDS, a total of 280 MDS-specific nonsynonymous single nucleotide variants were identified. By narrowing down with the single nucleotide polymorphism database, the functional missense database, and NCBI information, we finally identified three candidate mutations for EZH2, HECW2 and GATA-1, which may contribute to the evolution of the disease.

    DOI: 10.1007/s00277-014-2090-4

  • Inference of Gene Regulatory Networks Incorporating Multi-Source Biological Knowledge via a State Space Model with L1 Regularization 査読

    Takanori Hasegawa, Rui Yamaguchi, Masao Nagasaki, Satoru Miyano, Seiya Imoto

    PLOS ONE   9 ( 8 )   e105942 - e105942   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Comprehensive understanding of gene regulatory networks (GRNs) is a major challenge in the field of systems biology. Currently, there are two main approaches in GRN analysis using time-course observation data, namely an ordinary differential equation (ODE)-based approach and a statistical model-based approach. The ODE-based approach can generate complex dynamics of GRNs according to biologically validated nonlinear models. However, it cannot be applied to ten or more genes to simultaneously estimate system dynamics and regulatory relationships due to the computational difficulties. The statistical model-based approach uses highly abstract models to simply describe biological systems and to infer relationships among several hundreds of genes from the data. However, the high abstraction generates false regulations that are not permitted biologically. Thus, when dealing with several tens of genes of which the relationships are partially known, a method that can infer regulatory relationships based on a model with low abstraction and that can emulate the dynamics of ODE-based models while incorporating prior knowledge is urgently required. To accomplish this, we propose a method for inference of GRNs using a state space representation of a vector auto-regressive (VAR) model with L1 regularization. This method can estimate the dynamic behavior of genes based on linear time-series modeling constructed from an ODE-based model and can infer the regulatory structure among several tens of genes maximizing prediction ability for the observational data. Furthermore, the method is capable of incorporating various types of existing biological knowledge, e. g., drug kinetics and literature-recorded pathways. The effectiveness of the proposed method is shown through a comparison of simulation studies with several previous methods. For an application example, we evaluated mRNA expression profiles over time upon corticosteroid stimulation in rats, thus incorporating corticosteroid kinetics/dynamics, literature-recorded pathways and transcription factor (TF) information.

    DOI: 10.1371/journal.pone.0105942

  • Validation of multiple single nucleotide variation calls by additional exome analysis with a semiconductor sequencer to supplement data of whole-genome sequencing of a human population 査読

    Ikuko N. Motoike, Mitsuyo Matsumoto, Inaho Danjoh, Fumiki Katsuoka, Kaname Kojima, Naoki Nariai, Yukuto Sato, Yumi Yamaguchi-Kabata, Shin Ito, Hisaaki Kudo, Ichiko Nishijima, Satoshi Nishikawa, Xiaoqing Pan, Rumiko Saito, Sakae Saito, Tomo Saito, Matsuyuki Shirota, Kaoru Tsuda, Junji Yokozawa, Kazuhiko Igarashi, Naoko Minegishi, Osamu Tanabe, Nobuo Fuse, Masao Nagasaki, Kengo Kinoshita, Jun Yasuda, Masayuki Yamamoto

    BMC GENOMICS   15   673 - 673   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Validation of single nucleotide variations in whole-genome sequencing is critical for studying disease-related variations in large populations. A combination of different types of next-generation sequencers for analyzing individual genomes may be an efficient means of validating multiple single nucleotide variations calls simultaneously.
    Results: Here, we analyzed 12 independent Japanese genomes using two next-generation sequencing platforms: the Illumina HiSeq 2500 platform for whole-genome sequencing (average depth 32.4x), and the Ion Proton semiconductor sequencer for whole exome sequencing (average depth 109x). Single nucleotide polymorphism (SNP) calls based on the Illumina Human Omni 2.5-8 SNP chip data were used as the reference. We compared the variant calls for the 12 samples, and found that the concordance between the two next-generation sequencing platforms varied between 83% and 97%.
    Conclusions: Our results show the versatility and usefulness of the combination of exome sequencing with whole-genome sequencing in studies of human population genetics and demonstrate that combining data from multiple sequencing platforms is an efficient approach to validate and supplement SNP calls.

    DOI: 10.1186/1471-2164-15-673

  • SUGAR: graphical user interface-based data refiner for high-throughput DNA sequencing 査読

    Yukuto Sato, Kaname Kojima, Naoki Nariai, Yumi Yamaguchi-Kabata, Yosuke Kawai, Mamoru Takahashi, Takahiro Mimori, Masao Nagasaki

    BMC GENOMICS   15   664 - 664   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Next-generation sequencers (NGSs) have become one of the main tools for current biology. To obtain useful insights from the NGS data, it is essential to control low-quality portions of the data affected by technical errors such as air bubbles in sequencing fluidics.
    Results: We develop a software SUGAR (subtile-based GUI-assisted refiner) which can handle ultra-high-throughput data with user-friendly graphical user interface (GUI) and interactive analysis capability. The SUGAR generates high-resolution quality heatmaps of the flowcell, enabling users to find possible signals of technical errors during the sequencing. The sequencing data generated from the error-affected regions of a flowcell can be selectively removed by automated analysis or GUI-assisted operations implemented in the SUGAR. The automated data-cleaning function based on sequence read quality (Phred) scores was applied to a public whole human genome sequencing data and we proved the overall mapping quality was improved.
    Conclusion: The detailed data evaluation and cleaning enabled by SUGAR would reduce technical problems in sequence read mapping, improving subsequent variant analysis that require high-quality sequence data and mapping results. Therefore, the software will be especially useful to control the quality of variant calls to the low population cells, e.g., cancers, in a sample with technical errors of sequencing procedures.

    DOI: 10.1186/1471-2164-15-664

  • An efficient method of exploring simulation models by assimilating literature and biological observational data 査読

    Takanori Hasegawa, Masao Nagasaki, Rui Yamaguchi, Seiya Imoto, Satoru Miyano

    BIOSYSTEMS   121   54 - 66   2014年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recently, several biological simulation models of, e.g., gene regulatory networks and metabolic pathways, have been constructed based on existing knowledge of biomolecular reactions, e.g., DNA-protein and protein-protein interactions. However, since these do not always contain all necessary molecules and reactions, their simulation results can be inconsistent with observational data. Therefore, improvements in such simulation models are urgently required. A previously reported method created multiple candidate simulation models by partially modifying existing models. However, this approach was computationally costly and could not handle a large number of candidates that are required to find models whose simulation results are highly consistent with the data. In order to overcome the problem, we focused on the fact that the qualitative dynamics of simulation models are highly similar if they share a certain amount of regulatory structures. This indicates that better fitting candidates tend to share the basic regulatory structure of the best fitting candidate, which can best predict the data among candidates. Thus, instead of evaluating all candidates, we propose an efficient explorative method that can selectively and sequentially evaluate candidates based on the similarity of their regulatory structures. Furthermore, in estimating the parameter values of a candidate, e.g., synthesis and degradation rates of mRNA, for the data, those of the previously evaluated candidates can be utilized. The method is applied here to the pharmacogenomic pathways for corticosteroids in rats, using time-series microarray expression data. In the performance test, we succeeded in obtaining more than 80% of consistent solutions within 15% of the computational time as compared to the comprehensive evaluation. Then, we applied this approach to 142 literature-recorded simulation models of corticosteroid-induced genes, and consequently selected 134 newly constructed better models. The method described here was found to be capable of efficiently exploring candidate simulation models and obtaining better models within a short span of time. Furthermore, the results suggest that there may be room for improvement in literature recorded pathways and that they can be systematically updated using biological observational data. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.biosystems.2014.06.001

  • SVEM: A Structural Variant Estimation Method Using Multi-mapped Reads on Breakpoints 査読

    Tomohiko Ohtsuki, Naoki Nariai, Kaname Kojima, Takahiro Mimori, Yukuto Sato, Yosuke Kawai, Yumi Yamaguchi-Kabata, Testuo Shibuya, Masao Nagasaki

    ALGORITHMS FOR COMPUTATIONAL BIOLOGY   8542   208 - 219   2014年7月

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    記述言語:英語   掲載種別:研究論文(その他学術会議資料等)  

    Recent development of next generation sequencing (NGS) technologies has led to the identification of structural variants (SVs) of genomic DNA existing in the human population. Several SV detection methods utilizing NGS data have been proposed. However, there are several difficulties in analysis of NGS data, particularly with regard to handling reads from duplicated loci or low-complexity sequences of the human genome. In this paper, we propose SVEM, a novel statistical method to detect SVs with a single nucleotide resolution that can utilize multi-mapped reads on breakpoints. SVEM estimates the amount of reads on breakpoints as parameters and mapping states as latent variables using the expectation maximization algorithm. This framework enables us to handle ambiguous mapping of reads without discarding information for SV detection. SVEM is applied to simulation data and real data, and it achieves better performance than existing methods in terms of precision and recall.

  • CSML2SBML: A novel tool for converting quantitative biological pathway models from CSML into SBML 査読

    Chen Li, Masao Nagasaki, Emi Ikeda, Yayoi Sekiya, Satoru Miyano

    BIOSYSTEMS   121   22 - 28   2014年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    CSML and SBML are XML-based model definition standards which are developed with the aim of creating exchange formats for modeling, visualizing and simulating biological pathways. In this article we report a release of a format convertor for quantitative pathway models, namely CSML2SBML. It translates models encoded by CSML into SBML without loss of structural and kinetic information. The simulation and parameter estimation of the resulting SBML model can be carried out with compliant tool CellDesigner for further analysis. The convertor is based on the standards CSML version 3.0 and SBML Level 2 Version 4. In our experiments, 11 out of 15 pathway models in CSML model repository and 228 models in Macrophage Pathway Knowledgebase (MACPAK) are successfully converted to SBML models. The consistency of the resulting model is validated by libSBML Consistency Check of CellDesigner. Furthermore, the converted SBML model assigned with the kinetic parameters translated from CSML model can reproduce the same dynamics with CellDesigner as CSML one running on Cell Illustrator. CSML2SBML, along with its instructions and examples for use are available at http://csml2sbml.csml.org (C) 2014 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.biosystems.2014.05.004

  • iSVP: an integrated structural variant calling pipeline from high-throughput sequencing data 査読

    Takahiro Mimori, Naoki Nariai, Kaname Kojima, Mamoru Takahashi, Akira Ono, Yukuto Sato, Yumi Yamaguchi-Kabata, Masao Nagasaki

    BMC SYSTEMS BIOLOGY   7   S8 - S8   2013年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Structural variations (SVs), such as insertions, deletions, inversions, and duplications, are a common feature in human genomes, and a number of studies have reported that such SVs are associated with human diseases. Although the progress of next generation sequencing (NGS) technologies has led to the discovery of a large number of SVs, accurate and genome-wide detection of SVs remains challenging. Thus far, various calling algorithms based on NGS data have been proposed. However, their strategies are diverse and there is no tool able to detect a full range of SVs accurately.
    Results: We focused on evaluating the performance of existing deletion calling algorithms for various spanning ranges from low-to high-coverage simulation data. The simulation data was generated from a whole genome sequence with artificial SVs constructed based on the distribution of variants obtained from the 1000 Genomes Project. From the simulation analysis, deletion calls of various deletion sizes were obtained with each caller, and it was found that the performance was quite different according to the type of algorithms and targeting deletion size. Based on these results, we propose an integrated structural variant calling pipeline (iSVP) that combines existing methods with a newly devised filtering and merging processes. It achieved highly accurate deletion calling with >90% precision and >90% recall on the 30x read data for a broad range of size. We applied iSVP to the whole-genome sequence data of a CEU HapMap sample, and detected a large number of deletions, including notable peaks around 300 bp and 6,000 bp, which corresponded to Alus and long interspersed nuclear elements, respectively. In addition, many of the predicted deletions were highly consistent with experimentally validated ones by other studies.
    Conclusions: We present iSVP, a new deletion calling pipeline to obtain a genome-wide landscape of deletions in a highly accurate manner. From simulation and real data analysis, we show that iSVP is broadly applicable to human whole-genome sequencing data, which will elucidate relationships between SVs across genomes and associated diseases or biological functions.

    DOI: 10.1186/1752-0509-7-S6-S8

  • A statistical variant calling approach from pedigree information and local haplotyping with phase informative reads 査読

    Kaname Kojima, Naoki Nariai, Takahiro Mimori, Mamoru Takahashi, Yumi Yamaguchi-Kabata, Yukuto Sato, Masao Nagasaki

    BIOINFORMATICS   29 ( 22 )   2835 - 2843   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Motivation: Variant calling from genome-wide sequencing data is essential for the analysis of disease-causing mutations and elucidation of disease mechanisms. However, variant calling in low coverage regions is difficult due to sequence read errors and mapping errors. Hence, variant calling approaches that are robust to low coverage data are demanded.
    Results: We propose a new variant calling approach that considers pedigree information and haplotyping based on sequence reads spanning two or more heterozygous positions termed phase informative reads. In our approach, genotyping and haplotyping by the assignment of each read to a haplotype based on phase informative reads are simultaneously performed. Therefore, positions with low evidence for heterozygosity are rescued by phase informative reads, and such rescued positions contribute to haplotyping in a synergistic way. In addition, pedigree information supports more accurate haplotyping as well as genotyping, especially in low coverage regions. Although heterozygous positions are useful for haplotyping, homozygous positions are not informative and weaken the information from heterozygous positions, as majority of positions are homozygous. Thus, we introduce latent variables that determine zygosity at each position to filter out homozygous positions for haplotyping. In performance evaluation with a parent-offspring trio sequencing data, our approach outperforms existing approaches in accuracy on the agreement with single nucleotide polymorphism array genotyping results. Also, performance analysis considering distance between variants showed that the use of phase informative reads is effective for accurate variant calling, and further performance improvement is expected with longer sequencing data.

    DOI: 10.1093/bioinformatics/btt503

  • Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. 査読 国際誌

    Ayana Kon, Lee-Yung Shih, Masashi Minamino, Masashi Sanada, Yuichi Shiraishi, Yasunobu Nagata, Kenichi Yoshida, Yusuke Okuno, Masashige Bando, Ryuichiro Nakato, Shumpei Ishikawa, Aiko Sato-Otsubo, Genta Nagae, Aiko Nishimoto, Claudia Haferlach, Daniel Nowak, Yusuke Sato, Tamara Alpermann, Masao Nagasaki, Teppei Shimamura, Hiroko Tanaka, Kenichi Chiba, Ryo Yamamoto, Tomoyuki Yamaguchi, Makoto Otsu, Naoshi Obara, Mamiko Sakata-Yanagimoto, Tsuyoshi Nakamaki, Ken Ishiyama, Florian Nolte, Wolf-Karsten Hofmann, Shuichi Miyawaki, Shigeru Chiba, Hiraku Mori, Hiromitsu Nakauchi, H Phillip Koeffler, Hiroyuki Aburatani, Torsten Haferlach, Katsuhiko Shirahige, Satoru Miyano, Seishi Ogawa

    Nature genetics   45 ( 10 )   1232 - 7   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cohesin is a multimeric protein complex that is involved in the cohesion of sister chromatids, post-replicative DNA repair and transcriptional regulation. Here we report recurrent mutations and deletions involving multiple components of the cohesin complex, including STAG2, RAD21, SMC1A and SMC3, in different myeloid neoplasms. These mutations and deletions were mostly mutually exclusive and occurred in 12.1% (19/157) of acute myeloid leukemia, 8.0% (18/224) of myelodysplastic syndromes, 10.2% (9/88) of chronic myelomonocytic leukemia, 6.3% (4/64) of chronic myelogenous leukemia and 1.3% (1/77) of classical myeloproliferative neoplasms. Cohesin-mutated leukemic cells showed reduced amounts of chromatin-bound cohesin components, suggesting a substantial loss of cohesin binding sites on chromatin. The growth of leukemic cell lines harboring a mutation in RAD21 (Kasumi-1 cells) or having severely reduced expression of RAD21 and STAG2 (MOLM-13 cells) was suppressed by forced expression of wild-type RAD21 and wild-type RAD21 and STAG2, respectively. These findings suggest a role for compromised cohesin functions in myeloid leukemogenesis.

    DOI: 10.1038/ng.2731

  • Profiling of MicroRNA in Human and Mouse ES and iPS Cells Reveals Overlapping but Distinct MicroRNA Expression Patterns 査読

    Siti Razila Abdul Razak, Kazuko Ueno, Naoya Takayama, Naoki Nariai, Masao Nagasaki, Rika Saito, Hideto Koso, Chen-Yi Lai, Miyako Murakami, Koichiro Tsuji, Tatsuo Michiue, Hiromitsu Nakauchi, Makoto Otsu, Sumiko Watanabe

    PLOS ONE   8 ( 9 )   e73532 - e73532   2013年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Using quantitative PCR-based miRNA arrays, we comprehensively analyzed the expression profiles of miRNAs in human and mouse embryonic stem (ES), induced pluripotent stem (iPS), and somatic cells. Immature pluripotent cells were purified using SSEA-1 or SSEA-4 and were used for miRNA profiling. Hierarchical clustering and consensus clustering by nonnegative matrix factorization showed two major clusters, human ES/iPS cells and other cell groups, as previously reported. Principal components analysis (PCA) to identify miRNAs that segregate in these two groups identified miR-187, 299-3p, 499-5p, 628-5p, and 888 as new miRNAs that specifically characterize human ES/iPS cells. Detailed direct comparisons of miRNA expression levels in human ES and iPS cells showed that several miRNAs included in the chromosome 19 miRNA cluster were more strongly expressed in iPS cells than in ES cells. Similar analysis was conducted with mouse ES/iPS cells and somatic cells, and several miRNAs that had not been reported to be expressed in mouse ES/iPS cells were suggested to be ES/iPS cell-specific miRNAs by PCA. Comparison of the average expression levels of miRNAs in ES/iPS cells in humans and mice showed quite similar expression patterns of human/mouse miRNAs. However, several mouse-or human-specific miRNAs are ranked as high expressers. Time course tracing of miRNA levels during embryoid body formation revealed drastic and different patterns of changes in their levels. In summary, our miRNA expression profiling encompassing human and mouse ES and iPS cells gave various perspectives in understanding the miRNA core regulatory networks regulating pluripotent cells characteristics.

    DOI: 10.1371/journal.pone.0073532

  • TIGAR: transcript isoform abundance estimation method with gapped alignment of RNA-Seq data by variational Bayesian inference 査読

    Naoki Nariai, Osamu Hirose, Kaname Kojima, Masao Nagasaki

    BIOINFORMATICS   29 ( 18 )   2292 - 2299   2013年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Motivation: Many human genes express multiple transcript isoforms through alternative splicing, which greatly increases diversity of protein function. Although RNA sequencing (RNA-Seq) technologies have been widely used in measuring amounts of transcribed mRNA, accurate estimation of transcript isoform abundances from RNA-Seq data is challenging because reads often map to more than one transcript isoforms or paralogs whose sequences are similar to each other.
    Results: We propose a statistical method to estimate transcript isoform abundances from RNA-Seq data. Our method can handle gapped alignments of reads against reference sequences so that it allows insertion or deletion errors within reads. The proposed method optimizes the number of transcript isoforms by variational Bayesian inference through an iterative procedure, and its convergence is guaranteed under a stopping criterion. On simulated datasets, our method outperformed the comparable quantification methods in inferring transcript isoform abundances, and at the same time its rate of convergence was faster than that of the expectation maximization algorithm. We also applied our method to RNA-Seq data of human cell line samples, and showed that our prediction result was more consistent among technical replicates than those of other methods.

    DOI: 10.1093/bioinformatics/btt381

  • Wnt3a stimulates maturation of impaired neutrophils developed from severe congenital neutropenia patient-derived pluripotent stem cells 査読

    Takafumi Hiramoto, Yasuhiro Ebihara, Yoko Mizoguchi, Kazuhiro Nakamura, Kiyoshi Yamaguchi, Kazuko Ueno, Naoki Nariai, Shinji Mochizuki, Shohei Yamamoto, Masao Nagasaki, Yoichi Furukawa, Kenzaburo Tani, Hiromitsu Nakauchi, Masao Kobayashi, Kohichiro Tsuji

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   110 ( 8 )   3023 - 3028   2013年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The derivation of induced pluripotent stem (iPS) cells from individuals of genetic disorders offers new opportunities for basic research into these diseases and the development of therapeutic compounds. Severe congenital neutropenia (SCN) is a serious disorder characterized by severe neutropenia at birth. SCN is associated with heterozygous mutations in the neutrophil elastase [elastase, neutrophil-expressed (ELANE)] gene, but the mechanisms that disrupt neutrophil development have not yet been clarified because of the current lack of an appropriate disease model. Here, we generated iPS cells from an individual with SCN (SCN-iPS cells). Granulopoiesis from SCN-iPS cells revealed neutrophil maturation arrest and little sensitivity to granulocyte-colony stimulating factor, reflecting a disease status of SCN. Molecular analysis of the granulopoiesis from the SCN-iPS cells vs. control iPS cells showed reduced expression of genes related to the wingless-type mmtv integration site family, member 3a (Wnt3a)/beta-catenin pathway [e. g., lymphoid enhancer-binding factor 1], whereas Wnt3a administration induced elevation lymphoid enhancer-binding factor 1-expression and thematuration of SCN-iPS cell-derived neutrophils. These results indicate that SCN-iPS cells provide a useful disease model for SCN, and the activation of the Wnt3a/beta-catenin pathway may offer a novel therapy for SCN with ELANE mutation.

    DOI: 10.1073/pnas.1217039110

  • XiP: a computational environment to create, extend and share workflows 査読

    Masao Nagasaki, Andre Fujita, Yayoi Sekiya, Ayumu Saito, Emi Ikeda, Chen Li, Satoru Miyano

    BIOINFORMATICS   29 ( 1 )   137 - 139   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    XiP (eXtensible integrative Pipeline) is a flexible, editable and modular environment with a user-friendly interface that does not require previous advanced programming skills to run, construct and edit workflows. XiP allows the construction of workflows by linking components written in both R and Java, the analysis of high-throughput data in grid engine systems and also the development of customized pipelines that can be encapsulated in a package and distributed. XiP already comes with several ready-to-use pipeline flows for the most common genomic and transcriptomic analysis and similar to 300 computational components.

    DOI: 10.1093/bioinformatics/bts630

  • ChopSticks: High-resolution analysis of homozygous deletions by exploiting concordant read pairs 査読

    Tomohiro Yasuda, Shin Suzuki, Masao Nagasaki, Satoru Miyano

    BMC BIOINFORMATICS   13   279 - 279   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Structural variations (SVs) in genomes are commonly observed even in healthy individuals and play key roles in biological functions. To understand their functional impact or to infer molecular mechanisms of SVs, they have to be characterized with the maximum resolution. However, high-resolution analysis is a difficult task because it requires investigation of the complex structures involved in an enormous number of alignments of next-generation sequencing (NGS) reads and genome sequences that contain errors.
    Results: We propose a new method called ChopSticks that improves the resolution of SV detection for homozygous deletions even when the depth of coverage is low. Conventional methods based on read pairs use only discordant pairs to localize the positions of deletions, where a discordant pair is a read pair whose alignment has an aberrant strand or distance. In contrast, our method exploits concordant reads as well. We theoretically proved that when the depth of coverage approaches zero or infinity, the expected resolution of our method is asymptotically equal to that of methods based only on discordant pairs under double coverage. To confirm the effectiveness of ChopSticks, we conducted computational experiments against both simulated NGS reads and real NGS sequences. The resolution of deletion calls by other methods was significantly improved, thus demonstrating the usefulness of ChopSticks.
    Conclusions: ChopSticks can generate high-resolution deletion calls of homozygous deletions using information independent of other methods, and it is therefore useful to examine the functional impact of SVs or to infer SV generation mechanisms.

    DOI: 10.1186/1471-2105-13-279

  • Transposon mutagenesis identifies genes that transform neural stem cells into glioma-initiating cells 査読

    Hideto Koso, Haruna Takeda, Christopher Chin Kuan Yew, Jerrold M. Ward, Naoki Nariai, Kazuko Ueno, Masao Nagasaki, Sumiko Watanabe, Alistair G. Rust, David J. Adams, Neal G. Copeland, Nancy A. Jenkins

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   109 ( 44 )   E2998 - E3007   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neural stem cells (NSCs) are considered to be the cell of origin of glioblastoma multiforme (GBM). However, the genetic alterations that transform NSCs into glioma-initiating cells remain elusive. Using a unique transposon mutagenesis strategy that mutagenizes NSCs in culture, followed by additional rounds of mutagenesis to generate tumors in vivo, we have identified genes and signaling pathways that can transform NSCs into glioma-initiating cells. Mobilization of Sleeping Beauty transposons in NSCs induced the immortalization of astroglial-like cells, which were then able to generate tumors with characteristics of the mesenchymal subtype of GBM on transplantation, consistent with a potential astroglial origin for mesenchymal GBM. Sequence analysis of transposon insertion sites from tumors and immortalized cells identified more than 200 frequently mutated genes, including human GBM-associated genes, such as Met and Nf1, and made it possible to discriminate between genes that function during astroglial immortalization vs. later stages of tumor development. We also functionally validated five GBM candidate genes using a previously undescribed high-throughput method. Finally, we show that even clonally related tumors derived from the same immortalized line have acquired distinct combinations of genetic alterations during tumor development, suggesting that tumor formation in this model system involves competition among genetically variant cells, which is similar to the Darwinian evolutionary processes now thought to generate many human cancers. This mutagenesis strategy is faster and simpler than conventional transposon screens and can potentially be applied to any tissue stem/progenitor cells that can be grown and differentiated in vitro.

    DOI: 10.1073/pnas.1215899109

  • Epidermal Growth Factor Receptor Tyrosine Kinase Defines Critical Prognostic Genes of Stage I Lung Adenocarcinoma 査読

    Mai Yamauchi, Rui Yamaguchi, Asuka Nakata, Takashi Kohno, Masao Nagasaki, Teppei Shimamura, Seiya Imoto, Ayumu Saito, Kazuko Ueno, Yousuke Hatanaka, Ryo Yoshida, Tomoyuki Higuchi, Masaharu Nomura, David G. Beer, Jun Yokota, Satoru Miyano, Noriko Gotoh

    PLOS ONE   7 ( 9 )   e43923 - e43923   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Purpose: To identify stage I lung adenocarcinoma patients with a poor prognosis who will benefit from adjuvant therapy.
    Patients and Methods: Whole gene expression profiles were obtained at 19 time points over a 48-hour time course from human primary lung epithelial cells that were stimulated with epidermal growth factor (EGF) in the presence or absence of a clinically used EGF receptor tyrosine kinase (RTK)-specific inhibitor, gefitinib. The data were subjected to a mathematical simulation using the State Space Model (SSM). "Gefitinib-sensitive" genes, the expressional dynamics of which were altered by addition of gefitinib, were identified. A risk scoring model was constructed to classify high- or low-risk patients based on expression signatures of 139 gefitinib-sensitive genes in lung cancer using a training data set of 253 lung adenocarcinomas of North American cohort. The predictive ability of the risk scoring model was examined in independent cohorts of surgical specimens of lung cancer.
    Results: The risk scoring model enabled the identification of high-risk stage IA and IB cases in another North American cohort for overall survival (OS) with a hazard ratio (HR) of 7.16 (P = 0.029) and 3.26 (P = 0.0072), respectively. It also enabled the identification of high-risk stage I cases without bronchioalveolar carcinoma (BAC) histology in a Japanese cohort for OS and recurrence-free survival (RFS) with HRs of 8.79 (P = 0.001) and 3.72 (P = 0.0049), respectively.
    Conclusion: The set of 139 gefitinib-sensitive genes includes many genes known to be involved in biological aspects of cancer phenotypes, but not known to be involved in EGF signaling. The present result strongly re-emphasizes that EGF signaling status in cancer cells underlies an aggressive phenotype of cancer cells, which is useful for the selection of early-stage lung adenocarcinoma patients with a poor prognosis.

    DOI: 10.1371/journal.pone.0043923

  • A microarray analysis of gnotobiotic mice indicating that microbial exposure during the neonatal period plays an essential role in immune system development 査読

    Masahiro Yamamoto, Rui Yamaguchi, Kaori Munakata, Kiyoe Takashima, Mitsue Nishiyama, Kyoji Hioki, Yasuyuki Ohnishi, Masao Nagasaki, Seiya Imoto, Satoru Miyano, Atsushi Ishige, Kenji Watanabe

    BMC GENOMICS   13   335 - 335   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Epidemiological studies have suggested that the encounter with commensal microorganisms during the neonatal period is essential for normal development of the host immune system. Basic research involving gnotobiotic mice has demonstrated that colonization at the age of 5 weeks is too late to reconstitute normal immune function. In this study, we examined the transcriptome profiles of the large intestine (LI), small intestine (SI), liver (LIV), and spleen (SPL) of 3 bacterial colonization models-specific pathogen-free mice (SPF), ex-germ-free mice with bacterial reconstitution at the time of delivery (0WexGF), and ex-germ-free mice with bacterial reconstitution at 5 weeks of age (5WexGF)-and compared them with those of germ-free (GF) mice.
    Results: Hundreds of genes were affected in all tissues in each of the colonized models; however, a gene set enrichment analysis method, MetaGene Profiler (MGP), demonstrated that the specific changes of Gene Ontology (GO) categories occurred predominantly in 0WexGF LI, SPF SI, and 5WexGF SPL, respectively. MGP analysis on signal pathways revealed prominent changes in toll-like receptor (TLR)- and type 1 interferon (IFN)-signaling in LI of 0WexGF and SPF mice, but not 5WexGF mice, while 5WexGF mice showed specific changes in chemokine signaling. RT-PCR analysis of TLR-related genes showed that the expression of interferon regulatory factor 3 (Irf3), a crucial rate-limiting transcription factor in the induction of type 1 IFN, prominently decreased in 0WexGF and SPF mice but not in 5WexGF and GF mice.
    Conclusion: The present study provides important new information regarding the molecular mechanisms of the so-called "hygiene hypothesis".

    DOI: 10.1186/1471-2164-13-335

  • Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators 査読

    Akihiro Fujimoto, Yasushi Totoki, Tetsuo Abe, Keith A. Boroevich, Fumie Hosoda, Ha Hai Nguyen, Masayuki Aoki, Naoya Hosono, Michiaki Kubo, Fuyuki Miya, Yasuhito Arai, Hiroyuki Takahashi, Takuya Shirakihara, Masao Nagasaki, Tetsuo Shibuya, Kaoru Nakano, Kumiko Watanabe-Makino, Hiroko Tanaka, Hiromi Nakamura, Jun Kusuda, Hidenori Ojima, Kazuaki Shimada, Takuji Okusaka, Masaki Ueno, Yoshinobu Shigekawa, Yoshiiku Kawakami, Koji Arihiro, Hideki Ohdan, Kunihito Gotoh, Osamu Ishikawa, Shun-ichi Ariizumi, Masakazu Yamamoto, Terumasa Yamada, Kazuaki Chayama, Tomoo Kosuge, Hiroki Yamaue, Naoyuki Kamatani, Satoru Miyano, Hitoshi Nakagama, Yusuke Nakamura, Tatsuhiko Tsunoda, Tatsuhiro Shibata, Hidewaki Nakagawa

    NATURE GENETICS   44 ( 7 )   760 - U182   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. We sequenced and analyzed the whole genomes of 27 HCCs, 25 of which were associated with hepatitis B or C virus infections, including two sets of multicentric tumors. Although no common somatic mutations were identified in the multicentric tumor pairs, their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared etiological backgrounds may have strongly influenced their somatic mutation patterns. Statistical and functional analyses yielded a list of recurrently mutated genes. Multiple chromatin regulators, including ARID1A, ARID1B, ARID2, MLL and MLL3, were mutated in similar to 50% of the tumors. Hepatitis B virus genome integration in the TERT locus was frequently observed in a high clonal proportion. Our whole-genome sequencing analysis of HCCs identified the influence of etiological background on somatic mutation patterns and subsequent carcinogenesis, as well as recurrent mutations in chromatin regulators in HCCs.

    DOI: 10.1038/ng.2291

  • Identifying Gene Pathways Associated with Cancer Characteristics via Sparse Statistical Methods 査読

    Shuichi Kawano, Teppei Shimamura, Atsushi Niida, Seiya Imoto, Rui Yamaguchi, Masao Nagasaki, Ryo Yoshida, Cristin Print, Satoru Miyano

    IEEE-ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS   9 ( 4 )   966 - 972   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We propose a statistical method for uncovering gene pathways that characterize cancer heterogeneity. To incorporate knowledge of the pathways into the model, we define a set of activities of pathways from microarray gene expression data based on the Sparse Probabilistic Principal Component Analysis (SPPCA). A pathway activity logistic regression model is then formulated for cancer phenotype. To select pathway activities related to binary cancer phenotypes, we use the elastic net for the parameter estimation and derive a model selection criterion for selecting tuning parameters included in the model estimation. Our proposed method can also reverse-engineer gene networks based on the identified multiple pathways that enables us to discover novel gene-gene associations relating with the cancer phenotypes. We illustrate the whole process of the proposed method through the analysis of breast cancer gene expression data.

    DOI: 10.1109/TCBB.2012.48

  • IRView: a database and viewer for protein interacting regions 査読

    Shigeo Fujimori, Naoya Hirai, Kazuyo Masuoka, Tomohiro Oshikubo, Tatsuhiro Yamashita, Takanori Washio, Ayumu Saito, Masao Nagasaki, Satoru Miyano, Etsuko Miyamoto-Sato

    BIOINFORMATICS   28 ( 14 )   1949 - 1950   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Protein-protein interactions (PPIs) are mediated through specific regions on proteins. Some proteins have two or more protein interacting regions (IRs) and some IRs are competitively used for interactions with different proteins. IRView currently contains data for 3417 IRs in human and mouse proteins. The data were obtained from different sources and combined with annotated region data from InterPro. Information on non-synonymous single nucleotide polymorphism sites and variable regions owing to alternative mRNA splicing is also included. The IRView web interface displays all IR data, including user-uploaded data, on reference sequences so that the positional relationship between IRs can be easily understood. IRView should be useful for analyzing underlying relationships between the proteins behind the PPI networks.

    DOI: 10.1093/bioinformatics/bts289

  • ClipCrop: a tool for detecting structural variations with single-base resolution using soft-clipping information 査読

    Shin Suzuki, Tomohiro Yasuda, Yuichi Shiraishi, Satoru Miyano, Masao Nagasaki

    BMC BIOINFORMATICS   12   S7 - S7   2011年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Structural variations (SVs) change the structure of the genome and are therefore the causes of various diseases. Next-generation sequencing allows us to obtain a multitude of sequence data, some of which can be used to infer the position of SVs.
    Methods: We developed a new method and implementation named ClipCrop for detecting SVs with single-base resolution using soft-clipping information. A soft-clipped sequence is an unmatched fragment in a partially mapped read. To assess the performance of ClipCrop with other SV-detecting tools, we generated various patterns of simulation data - SV lengths, read lengths, and the depth of coverage of short reads - with insertions, deletions, tandem duplications, inversions and single nucleotide alterations in a human chromosome. For comparison, we selected BreakDancer, CNVnator and Pindel, each of which adopts a different approach to detect SVs, e. g. discordant pair approach, depth of coverage approach and split read approach, respectively.
    Results: Our method outperformed BreakDancer and CNVnator in both discovering rate and call accuracy in any type of SV. Pindel offered a similar performance as our method, but our method crucially outperformed for detecting small duplications. From our experiments, ClipCrop infer reliable SVs for the data set with more than 50 bases read lengths and 20x depth of coverage, both of which are reasonable values in current NGS data set.
    Conclusions: ClipCrop can detect SVs with higher discovering rate and call accuracy than any other tool in our simulation data set.

    DOI: 10.1186/1471-2105-12-S14-S7

  • High Performance Hybrid Functional Petri Net Simulations of Biological Pathway Models on CUDA 査読

    Georgios Chalkidis, Masao Nagasaki, Satoru Miyano

    IEEE-ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS   8 ( 6 )   1545 - 1556   2011年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hybrid functional Petri nets are a wide-spread tool for representing and simulating biological models. Due to their potential of providing virtual drug testing environments, biological simulations have a growing impact on pharmaceutical research. Continuous research advancements in biology and medicine lead to exponentially increasing simulation times, thus raising the demand for performance accelerations by efficient and inexpensive parallel computation solutions. Recent developments in the field of general-purpose computation on graphics processing units (GPGPU) enabled the scientific community to port a variety of compute intensive algorithms onto the graphics processing unit (GPU). This work presents the first scheme for mapping biological hybrid functional Petri net models, which can handle both discrete and continuous entities, onto compute unified device architecture (CUDA) enabled GPUs. GPU accelerated simulations are observed to run up to 18 times faster than sequential implementations. Simulating the cell boundary formation by Delta-Notch signaling on a CUDA enabled GPU results in a speedup of approximately 7x for a model containing 1,600 cells.

    DOI: 10.1109/TCBB.2010.118

  • Frequent pathway mutations of splicing machinery in myelodysplasia 査読

    Kenichi Yoshida, Masashi Sanada, Yuichi Shiraishi, Daniel Nowak, Yasunobu Nagata, Ryo Yamamoto, Yusuke Sato, Aiko Sato-Otsubo, Ayana Kon, Masao Nagasaki, George Chalkidis, Yutaka Suzuki, Masashi Shiosaka, Ryoichiro Kawahata, Tomoyuki Yamaguchi, Makoto Otsu, Naoshi Obara, Mamiko Sakata-Yanagimoto, Ken Ishiyama, Hiraku Mori, Florian Nolte, Wolf-Karsten Hofmann, Shuichi Miyawaki, Sumio Sugano, Claudia Haferlach, H. Phillip Koeffler, Lee-Yung Shih, Torsten Haferlach, Shigeru Chiba, Hiromitsu Nakauchi, Satoru Miyano, Seishi Ogawa

    NATURE   478 ( 7367 )   64 - 69   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Myelodysplastic syndromes and related disorders (myelodysplasia) are a heterogeneous group of myeloid neoplasms showing deregulated blood cell production with evidence of myeloid dysplasia and a predisposition to acute myeloid leukaemia, whose pathogenesis is only incompletely understood. Here we report whole-exome sequencing of 29 myelodysplasia specimens, which unexpectedly revealed novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1. In a large series analysis, these splicing pathway mutations were frequent (similar to 45 to similar to 85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia. Conspicuously, most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 3'-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis. Our results provide the first evidence indicating that genetic alterations of the major splicing components could be involved inhuman pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.

    DOI: 10.1038/nature10496

  • CSO validator: improving manual curation workflow for biological pathways 査読

    Euna Jeong, Masao Nagasaki, Emi Ikeda, Yayoi Sekiya, Ayumu Saito, Satoru Miyano

    BIOINFORMATICS   27 ( 17 )   2471 - 2472   2011年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Manual curation and validation of large-scale biological pathways are required to obtain high-quality pathway databases. In a typical curation process, model validation and model update based on appropriate feedback are repeated and requires considerable cooperation of scientists. We have developed a CSO (Cell System Ontology) validator to reduce the repetition and time during the curation process. This tool assists in quickly obtaining agreement among curators and domain experts and in providing a consistent and accurate pathway database.

    DOI: 10.1093/bioinformatics/btr395

  • Hybrid Petri net based modeling for biological pathway simulation 査読

    Hiroshi Matsuno, Masao Nagasaki, Satoru Miyano

    NATURAL COMPUTING   10 ( 3 )   1099 - 1120   2011年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hybrid Petri net (HPN) is an extension of the Petri net formalism, which enables us to handle continuous information in addition to discrete information. Firstly, this paper demonstrates how biological pathways can be modeled by the integration of discrete and continuous elements, with an example of the lambda phage genetic switch system including induction and retroregulation mechanisms. Although HPN allows intuitive modeling of biological pathways, some fundamental biological processes such as complex formation cannot be represented with HPN. Thus, this paper next provides the formal definition of hybrid functional Petri net with extension (HFPNe), which has high potential for modeling various kinds of biological processes. Cell Illustrator is a software tool developed on the basis of the definition of HFPNe. Hypothesis creation by Cell Illustrator is demonstrated with the example of the cyanobacterial circadian gene clock system. Finally, our ongoing tasks, which include the development of a computational platform for systems biology, are presented.

    DOI: 10.1007/s11047-009-9164-6

  • A Novel Network Profiling Analysis Reveals System Changes in Epithelial-Mesenchymal Transition 査読

    Teppei Shimamura, Seiya Imoto, Yukako Shimada, Yasuyuki Hosono, Atsushi Niida, Masao Nagasaki, Rui Yamaguchi, Takashi Takahashi, Satoru Miyano

    PLOS ONE   6 ( 6 )   e20804 - e20804   2011年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Patient-specific analysis of molecular networks is a promising strategy for making individual risk predictions and treatment decisions in cancer therapy. Although systems biology allows the gene network of a cell to be reconstructed from clinical gene expression data, traditional methods, such as Bayesian networks, only provide an averaged network for all samples. Therefore, these methods cannot reveal patient-specific differences in molecular networks during cancer progression. In this study, we developed a novel statistical method called NetworkProfiler, which infers patient-specific gene regulatory networks for a specific clinical characteristic, such as cancer progression, from gene expression data of cancer patients. We applied NetworkProfiler to microarray gene expression data from 762 cancer cell lines and extracted the system changes that were related to the epithelial-mesenchymal transition (EMT). Out of 1732 possible regulators of E-cadherin, a cell adhesion molecule that modulates the EMT, NetworkProfiler, identified 25 candidate regulators, of which about half have been experimentally verified in the literature. In addition, we used NetworkProfiler to predict EMT-dependent master regulators that enhanced cell adhesion, migration, invasion, and metastasis. In order to further evaluate the performance of NetworkProfiler, we selected Krueppel-like factor 5 (KLF5) from a list of the remaining candidate regulators of E-cadherin and conducted in vitro validation experiments. As a result, we found that knockdown of KLF5 by siRNA significantly decreased E-cadherin expression and induced morphological changes characteristic of EMT. In addition, in vitro experiments of a novel candidate EMT-related microRNA, miR-100, confirmed the involvement of miR-100 in several EMT-related aspects, which was consistent with the predictions obtained by NetworkProfiler.

    DOI: 10.1371/journal.pone.0020804

  • Systems biology model repository for macrophage pathway simulation 査読

    Masao Nagasaki, Ayumu Saito, Andre Fujita, Georg Tremmel, Kazuko Ueno, Emi Ikeda, Euna Jeong, Satoru Miyano

    BIOINFORMATICS   27 ( 11 )   1591 - 1593   2011年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The Macrophage Pathway Knowledgebase (MACPAK) is a computational system that allows biomedical researchers to query and study the dynamic behaviors of macrophage molecular pathways. It integrates the knowledge of 230 reviews that were carefully checked by specialists for their accuracy and then converted to 230 dynamic mathematical pathway models. MACPAK comprises a total of 24 009 entities and 12 774 processes and is described in the Cell System Markup Language (CSML), an XML format that runs on the Cell Illustrator platform and can be visualized with a customized Cytoscape for further analysis.

    DOI: 10.1093/bioinformatics/btr173

  • Estimating Genome-Wide Gene Networks Using Nonparametric Bayesian Network Models on Massively Parallel Computers 査読

    Y Tamada, S Imoto, H Araki, M Nagasaki, C Print, D S Charnock-Jones, S Miyano

    IEEE/ACM Transactions on Computational Biology and Bioinformatics   8 ( 3 )   683 - 697   2011年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1109/tcbb.2010.68

  • Comprehensive Pharmacogenomic Pathway Screening by Data Assimilation 査読

    Takanori Hasegawa, Rui Yamaguchi, Masao Nagasaki, Seiya Imoto, Satoru Miyano

    BIOINFORMATICS RESEARCH AND APPLICATIONS   6674   160 - 171   2011年5月

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    記述言語:英語   掲載種別:研究論文(その他学術会議資料等)  

    We propose a computational method to comprehensively screen for pharmacogenomic pathway simulation models. A systematic model generation strategy is developed; candidate pharmacogenomic models are automatically generated from some prototype models constructed from existing literature. The parameters in the model are automatically estimated based on time-course observed gene expression data by data assimilation technique. The candidate simulation models are also ranked based on their prediction power measured by Bayesian information criterion. We generated 53 pharmacogenomic simulation models from five prototypes and applied the proposed method to microarray gene expression data of rat liver cells treated with corticosteroid. We found that some extended simulation models have higher prediction power for some genes than the original models.

  • MIRACH: efficient model checker for quantitative biological pathway models 査読

    Chuan Hock Koh, Masao Nagasaki, Ayumu Saito, Chen Li, Limsoon Wong, Satoru Miyano

    BIOINFORMATICS   27 ( 5 )   734 - 735   2011年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Model checking is playing an increasingly important role in systems biology as larger and more complex biological pathways are being modeled. In this article we report the release of an efficient model checker MIRACH 1.0, which supports any model written in popular formats such as CSML and SBML. MIRACH is integrated with a Petri-net-based simulation engine, enabling efficient online (on-the-fly) checking. In our experiment, by using Levchenko et al. model, we reveal that timesaving gains by using MIRACH easily surpass 400% compared with its offline-based counterpart.

    DOI: 10.1093/bioinformatics/btq727

  • Ontology-based instance data validation for high-quality curated biological pathways 査読

    Euna Jeong, Masao Nagasaki, Kazuko Ueno, Satoru Miyano

    BMC BIOINFORMATICS   12   S8 - S8   2011年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Modeling in systems biology is vital for understanding the complexity of biological systems across scales and predicting system-level behaviors. To obtain high-quality pathway databases, it is essential to improve the efficiency of model validation and model update based on appropriate feedback.
    Results: We have developed a new method to guide creating novel high-quality biological pathways, using a rule-based validation. Rules are defined to correct models against biological semantics and improve models for dynamic simulation. In this work, we have defined 40 rules which constrain event-specific participants and the related features and adding missing processes based on biological events. This approach is applied to data in Cell System Ontology which is a comprehensive ontology that represents complex biological pathways with dynamics and visualization. The experimental results show that the relatively simple rules can efficiently detect errors made during curation, such as misassignment and misuse of ontology concepts and terms in curated models.
    Conclusions: A new rule-based approach has been developed to facilitate model validation and model complementation. Our rule-based validation embedding biological semantics enables us to provide high-quality curated biological pathways. This approach can serve as a preprocessing step for model integration, exchange and extraction data, and simulation.

    DOI: 10.1186/1471-2105-12-S1-S8

  • Cell illustrator 4.0: a computational platform for systems biology. 査読 国際誌

    Nagasaki M, Saito A, Jeong E, Li C, Kojima K, Ikeda E, Miyano S

    Studies in health technology and informatics   162   160 - 181   2011年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cell illustrator 4.0: a computational platform for systems biology.
    Cell Illustrator is a software platform for Systems Biology that uses the concept of Petri net for modeling and simulating biopathways. It is intended for biological scientists working at bench. The latest version of Cell Illustrator 4.0 uses Java Web Start technology and is enhanced with new capabilities, including: automatic graph grid layout algorithms using ontology information; tools using Cell System Markup Language (CSML) 3.0 and Cell System Ontology 3.0; parameter search module; high-performance simulation module; CSML database management system; conversion from CSML model to programming languages (FORTRAN, C, C++, Java, Python and Perl); import from SBML, CellML, and BioPAX; and, export to SVG and HTML. Cell Illustrator employs an extension of hybrid Petri net in an object-oriented style so that biopathway models can include objects such as DNA sequence, molecular density, 3D localization information, transcription with frame-shift, translation with codon table, as well as biochemical reactions.

  • Model-free unsupervised gene set screening based on information enrichment in expression profiles 査読

    Atushi Niida, Seiya Imoto, Rui Yamaguchi, Masao Nagasaki, Andre Fujita, Teppei Shimamura, Satoru Miyano

    BIOINFORMATICS   26 ( 24 )   3090 - 3097   2010年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Motivation: A number of unsupervised gene set screening methods have recently been developed for search of putative functional gene sets based on their expression profiles. Most of the methods statistically evaluate whether the expression profiles of each gene set are fit to assumed models: e. g. co-expression across all samples or a subgroup of samples. However, it is possible that they fail to capture informative gene sets whose expression profiles are not fit to the assumed models.
    Results: To overcome this limitation, we propose a model-free unsupervised gene set screening method, Matrix Information Enrichment Analysis (MIEA). Without assuming any specific models, MIEA screens gene sets based on information richness of their expression profiles. We extensively compared the performance of MIEA to those of other unsupervised gene set screening methods, using various types of simulated and real data. The benchmark tests demonstrated that MIEA can detect singular expression profiles that the other methods fail to find, and performs broadly well for various types of input data. Taken together, this study introduces MIEA as a broadly applicable gene set screening tool for mining regulatory programs from transcriptome data.

    DOI: 10.1093/bioinformatics/btq592

  • Phosphoproteomics-Based Modeling Defines the Regulatory Mechanism Underlying Aberrant EGFR Signaling 査読

    Shinya Tasaki, Masao Nagasaki, Hiroko Kozuka-Hata, Kentaro Semba, Noriko Gotoh, Seisuke Hattori, Jun-ichiro Inoue, Tadashi Yamamoto, Satoru Miyano, Sumio Sugano, Masaaki Oyama

    PLOS ONE   5 ( 11 )   e13926 - e13926   2010年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Mutation of the epidermal growth factor receptor (EGFR) results in a discordant cell signaling, leading to the development of various diseases. However, the mechanism underlying the alteration of downstream signaling due to such mutation has not yet been completely understood at the system level. Here, we report a phosphoproteomics-based methodology for characterizing the regulatory mechanism underlying aberrant EGFR signaling using computational network modeling.
    Methodology/Principal Findings: Our phosphoproteomic analysis of the mutation at tyrosine 992 (Y992), one of the multifunctional docking sites of EGFR, revealed network-wide effects of the mutation on EGF signaling in a time-resolved manner. Computational modeling based on the temporal activation profiles enabled us to not only rediscover already-known protein interactions with Y992 and internalization property of mutated EGFR but also further gain model-driven insights into the effect of cellular content and the regulation of EGFR degradation. Our kinetic model also suggested critical reactions facilitating the reconstruction of the diverse effects of the mutation on phosphoproteome dynamics.
    Conclusions/Significance: Our integrative approach provided a mechanistic description of the disorders of mutated EGFR signaling networks, which could facilitate the development of a systematic strategy toward controlling disease-related cell signaling.

    DOI: 10.1371/journal.pone.0013926

  • Whole-genome sequencing and comprehensive variant analysis of a Japanese individual using massively parallel sequencing 査読

    Akihiro Fujimoto, Hidewaki Nakagawa, Naoya Hosono, Kaoru Nakano, Tetsuo Abe, Keith A. Boroevich, Masao Nagasaki, Rui Yamaguchi, Tetsuo Shibuya, Michiaki Kubo, Satoru Miyano, Yusuke Nakamura, Tatsuhiko Tsunoda

    NATURE GENETICS   42 ( 11 )   931 - U39   2010年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We report the analysis of a Japanese male using high-throughput sequencing to x40 coverage. More than 99% of the sequence reads were mapped to the reference human genome. Using a Bayesian decision method, we identified 3,132,608 single nucleotide variations (SNVs). Comparison with six previously reported genomes revealed an excess of singleton nonsense and nonsynonymous SNVs, as well as singleton SNVs in conserved non-coding regions. We also identified 5,319 deletions smaller than 10 kb with high accuracy, in addition to copy number variations and rearrangements. De novo assembly of the unmapped sequence reads generated around 3 Mb of novel sequence, which showed high similarity to non-reference human genomes and the human herpesvirus 4 genome. Our analysis suggests that considerable variation remains undiscovered in the human genome and that whole-genome sequencing is an invaluable tool for obtaining a complete understanding of human genetic variation.

    DOI: 10.1038/ng.691

  • Identification of granger causality between gene sets 査読

    André Fujita, João Ricardo Sato, Kaname Kojima, Luciana Rodrigues Gomes, Masao Nagasaki, Mari Cleide Sogayar, Satoru Miyano

    Journal of Bioinformatics and Computational Biology   8 ( 4 )   679 - 701   2010年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Wiener and Granger have introduced an intuitive concept of causality (Granger causality) between two variables which is based on the idea that an effect never occurs before its cause. Later, Geweke generalized this concept to a multivariate Granger causality, i.e. n variables Granger-cause another variable. Although Granger causality is not "effective causality" in the Aristothelic sense, this concept is useful to infer directionality and information flow in observational data. Granger causality is usually identified by using VAR (Vector Autoregressive) models due to their simplicity. In the last few years, several VAR-based models were presented in order to model gene regulatory networks. Here, we generalize the multivariate Granger causality concept in order to identify Granger causalities between sets of gene expressions, i.e. whether a set of n genes Granger-causes another set of m genes, aiming at identifying the flow of information between gene networks (or pathways). The concept of Granger causality for sets of variables is presented. Moreover, a method for its identification with a bootstrap test is proposed. This method is applied in simulated and also in actual biological gene expression data in order to model regulatory networks. This concept may be useful for the understanding of the complete information flow from one network or pathway to the other, mainly in regulatory networks. Linking this concept to graph theory, sink and source can be generalized to node sets. Moreover, hub and centrality for sets of genes can be defined based on total information flow. Another application is in annotation, when the functionality of a set of genes is unknown, but this set is Granger-caused by another set of genes which is well studied. Therefore, this information may be useful to infer or construct some hypothesis about the unknown set of genes. © 2010 Imperial College Press.

    DOI: 10.1142/S0219720010004860

  • DA 1.0: parameter estimation of biological pathways using data assimilation approach 査読

    Chuan Hock Koh, Masao Nagasaki, Ayumu Saito, Limsoon Wong, Satoru Miyano

    BIOINFORMATICS   26 ( 14 )   1794 - 1796   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Data assimilation (DA) is a computational approach that estimates unknown parameters in a pathway model using time-course information. Particle filtering, the underlying method used, is a well-established statistical method that approximates the joint posterior distributions of parameters by using sequentially generated Monte Carlo samples. In this article, we report the release of Java-based software (DA 1.0) with an intuitive and user-friendly interface to allow users to carry out parameters estimation using DA.

    DOI: 10.1093/bioinformatics/btq276

  • An efficient biological pathway layout algorithm combining grid-layout and spring embedder for complicated cellular location information 査読

    Kaname Kojima, Masao Nagasaki, Satoru Miyano

    BMC BIOINFORMATICS   11   335 - 335   2010年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Graph drawing is one of the important techniques for understanding biological regulations in a cell or among cells at the pathway level. Among many available layout algorithms, the spring embedder algorithm is widely used not only for pathway drawing but also for circuit placement and www visualization and so on because of the harmonized appearance of its results. For pathway drawing, location information is essential for its comprehension. However, complex shapes need to be taken into account when torus-shaped location information such as nuclear inner membrane, nuclear outer membrane, and plasma membrane is considered. Unfortunately, the spring embedder algorithm cannot easily handle such information. In addition, crossings between edges and nodes are usually not considered explicitly.
    Results: We proposed a new grid-layout algorithm based on the spring embedder algorithm that can handle location information and provide layouts with harmonized appearance. In grid-layout algorithms, the mapping of nodes to grid points that minimizes a cost function is searched. By imposing positional constraints on grid points, location information including complex shapes can be easily considered. Our layout algorithm includes the spring embedder cost as a component of the cost function. We further extend the layout algorithm to enable dynamic update of the positions and sizes of compartments at each step.
    Conclusions: The new spring embedder-based grid-layout algorithm and a spring embedder algorithm are applied to three biological pathways; endothelial cell model, Fas-induced apoptosis model, and C. elegans cell fate simulation model. From the positional constraints, all the results of our algorithm satisfy location information, and hence, more comprehensible layouts are obtained as compared to the spring embedder algorithm. From the comparison of the number of crossings, the results of the grid-layout-based algorithm tend to contain more crossings than those of the spring embedder algorithm due to the positional constraints. For a fair comparison, we also apply our proposed method without positional constraints. This comparison shows that these results contain less crossings than those of the spring embedder algorithm. We also compared layouts of the proposed algorithm with and without compartment update and verified that latter can reach better local optima.

    DOI: 10.1186/1471-2105-11-335

  • The systems approach to the prespore-specific activation of sigma factor SigF in Bacillus subtilis 査読

    Jin Hwan Do, Masao Nagasaki, Satoru Miyano

    BIOSYSTEMS   100 ( 3 )   178 - 184   2010年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The prespore-specific activation of sigma factor SigF (sigma(F)) in Bacillus subtilis has been explained mainly by two factors, i.e., the transient genetic asymmetry and the volume difference between the mother cell and the prespore. Here, we systematically surveyed the effect of these two factors on sporulation using a quantitative modeling and simulation architecture named hybrid functional Petri net with extension (HFPNe). Considering the fact that the transient genetic asymmetry and the volume difference in sporulation of B. subtilis finally bring about the concentration difference in two proteins SpoIIAB (AB) and SpoIIAA (AA) between the mother cell and the prespore, we have surveyed the effect of AB and AA concentration on the prespore-specific activation of sigma(F) occurring in the early stage of sporulation. Our results show that the prespore-specific activation of sigma(F) could be governed by the ratio of AA to AB rather than their concentrations themselves. Our model also suggests that B. subtilis could maximize the ratio of AA to AB in the prespore and minimize it in the mother cell by employing both the transient genetic asymmetry and the volume difference simultaneously. This might give a good explanation to the co-occurrence of the transient asymmetry and the volume difference during sporulation of B. subtilis. In addition, we suggest for the first time that the sigma(F) activation in the prespore might be switched off by the decrease in the ratio of AA to AB after the transient genetic asymmetry is to an end by completion of DNA translocation into the prespore. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.biosystems.2010.03.002

  • Gene Set-Based Module Discovery Decodes cis-Regulatory Codes Governing Diverse Gene Expression across Human Multiple Tissues 査読

    Atsushi Niida, Seiya Imoto, Rui Yamaguchi, Masao Nagasaki, Satoru Miyano

    PLOS ONE   5 ( 6 )   e10910 - e10910   2010年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Decoding transcriptional programs governing transcriptomic diversity across human multiple tissues is a major challenge in bioinformatics. To address this problem, a number of computational methods have focused on cis-regulatory codes driving overexpression or underexpression in a single tissue as compared to others. On the other hand, we recently proposed a different approach to mine cis-regulatory codes: starting from gene sets sharing common cis-regulatory motifs, the method screens for expression modules based on expression coherence. However, both approaches seem to be insufficient to capture transcriptional programs that control gene expression in a subset of all samples. Especially, this limitation would be serious when analyzing multiple tissue data. To overcome this limitation, we developed a new module discovery method termed BEEM (Biclusering-based Extraction of Expression Modules) in order to discover expression modules that are functional in a subset of tissues. We showed that, when applied to expression profiles of human multiple tissues, BEEM finds expression modules missed by two existing approaches that are based on the coherent expression and the single tissue-specific differential expression. From the BEEM results, we obtained new insights into transcriptional programs controlling transcriptomic diversity across various types of tissues. This study introduces BEEM as a powerful tool for decoding regulatory programs from a compendium of gene expression profiles.

    DOI: 10.1371/journal.pone.0010910

  • Inferring dynamic gene networks under varying conditions for transcriptomic network comparison 査読

    Teppei Shimamura, Seiya Imoto, Rui Yamaguchi, Masao Nagasaki, Satoru Miyano

    BIOINFORMATICS   26 ( 8 )   1064 - 1072   2010年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Motivation: Elucidating the differences between cellular responses to various biological conditions or external stimuli is an important challenge in systems biology. Many approaches have been developed to reverse engineer a cellular system, called gene network, from time series microarray data in order to understand a transcriptomic response under a condition of interest. Comparative topological analysis has also been applied based on the gene networks inferred independently from each of the multiple time series datasets under varying conditions to find critical differences between these networks. However, these comparisons often lead to misleading results, because each network contains considerable noise due to the limited length of the time series.
    Results: We propose an integrated approach for inferring multiple gene networks from time series expression data under varying conditions. To the best of our knowledge, our approach is the first reverse-engineering method that is intended for transcriptomic network comparison between varying conditions. Furthermore, we propose a state-of-the-art parameter estimation method, relevance-weighted recursive elastic net, for providing higher precision and recall than existing reverse-engineering methods. We analyze experimental data of MCF-7 human breast cancer cells stimulated by epidermal growth factor or heregulin with several doses and provide novel biological hypotheses through network comparison.

    DOI: 10.1093/bioinformatics/btq080

  • Time-dependent structural transformation analysis to high-level Petri net model with active state transition diagram 査読

    Chen Li, Masao Nagasaki, Ayumu Saito, Satoru Miyano

    BMC SYSTEMS BIOLOGY   4   39 - 39   2010年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: With an accumulation of in silico data obtained by simulating large-scale biological networks, a new interest of research is emerging for elucidating how living organism functions over time in cells. Investigating the dynamic features of current computational models promises a deeper understanding of complex cellular processes. This leads us to develop a method that utilizes structural properties of the model over all simulation time steps. Further, user-friendly overviews of dynamic behaviors can be considered to provide a great help in understanding the variations of system mechanisms.
    Results: We propose a novel method for constructing and analyzing a so-called active state transition diagram (ASTD) by using time-course simulation data of a high-level Petri net. Our method includes two new algorithms. The first algorithm extracts a series of subnets (called temporal subnets) reflecting biological components contributing to the dynamics, while retaining positive mathematical qualities. The second one creates an ASTD composed of unique temporal subnets. ASTD provides users with concise information allowing them to grasp and trace how a key regulatory subnet and/or a network changes with time. The applicability of our method is demonstrated by the analysis of the underlying model for circadian rhythms in Drosophila.
    Conclusions: Building ASTD is a useful means to convert a hybrid model dealing with discrete, continuous and more complicated events to finite time-dependent states. Based on ASTD, various analytical approaches can be applied to obtain new insights into not only systematic mechanisms but also dynamics.

    DOI: 10.1186/1752-0509-4-39

  • A novel meta-analysis approach of cancer transcriptomes reveals prevailing transcriptional networks in cancer cells. 査読

    Atsushi Niida, Seiya Imoto, Masao Nagasaki, Rui Yamaguchi, Satoru Miyano

    Genome informatics. International Conference on Genome Informatics   22   121 - 31   2010年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although microarray technology has revealed transcriptomic diversities underlining various cancer phenotypes, transcriptional programs controlling them have not been well elucidated. To decode transcriptional programs governing cancer transcriptomes, we have recently developed a computational method termed EEM, which searches for expression modules from prescribed gene sets defined by prior biological knowledge like TF binding motifs. In this paper, we extend our EEM approach to predict cancer transcriptional networks. Starting from functional TF binding motifs and expression modules identified by EEM, we predict cancer transcriptional networks containing regulatory TFs, associated GO terms, and interactions between TF binding motifs. To systematically analyze transcriptional programs in broad types of cancer, we applied our EEM-based network prediction method to 122 microarray datasets collected from public databases. The data sets contain about 15000 experiments for tumor samples of various tissue origins including breast, colon, lung etc. This EEM based meta-analysis successfully revealed a prevailing cancer transcriptional network which functions in a large fraction of cancer transcriptomes; they include cell-cycle and immune related sub-networks. This study demonstrates broad applicability of EEM, and opens a way to comprehensive understanding of transcriptional networks in cancer cells.

  • A state space representation of VAR models with sparse learning for dynamic gene networks. 査読

    Kojima K, Yamaguchi R, Imoto S, Yamauchi M, Nagasaki M, Yoshida R, Shimamura T, Ueno K, Higuchi T, Gotoh N, Miyano S

    Genome informatics. International Conference on Genome Informatics   22   56 - 68   2010年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A state space representation of VAR models with sparse learning for dynamic gene networks.
    We propose a state space representation of vector autoregressive model and its sparse learning based on L1 regularization to achieve efficient estimation of dynamic gene networks based on time course microarray data. The proposed method can overcome drawbacks of the vector autoregressive model and state space model; the assumption of equal time interval and lack of separation ability of observation and systems noises in the former method and the assumption of modularity of network structure in the latter method. However, in a simple implementation the proposed model requires the calculation of large inverse matrices in a large number of times during parameter estimation process based on EM algorithm. This limits the applicability of the proposed method to a relatively small gene set. We thus introduce a new calculation technique for EM algorithm that does not require the calculation of inverse matrices. The proposed method is applied to time course microarray data of lung cells treated by stimulating EGF receptors and dosing an anticancer drug, Gefitinib. By comparing the estimated network with the control network estimated using non-treated lung cells, perturbed genes by the anticancer drug could be found, whose up- and down-stream genes in the estimated networks may be related to side effects of the anticancer drug.

  • Ligand-based gene expression profiling reveals novel roles of glucocorticoid receptor in cardiac metabolism 査読

    Noritada Yoshikawa, Masao Nagasaki, Motoaki Sano, Satori Tokudome, Kazuko Ueno, Noriaki Shimizu, Seiya Imoto, Satoru Miyano, Makoto Suematsu, Keiichi Fukuda, Chikao Morimoto, Hirotoshi Tanaka

    AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM   296 ( 6 )   E1363 - E1373   2009年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Yoshikawa N, Nagasaki M, Sano M, Tokudome S, Ueno K, Shimizu N, Imoto S, Miyano S, Suematsu M, Fukuda K, Morimoto C, Tanaka H. Ligand-based gene expression profiling reveals novel roles of glucocorticoid receptor in cardiac metabolism. Am J Physiol Endocrinol Metab 296: E1363-E1373, 2009. First published March 17, 2009; doi:10.1152/ajpendo.90767.2008.-Recent studies have documented various roles of adrenal corticosteroid signaling in cardiac physiology and pathophysiology. It is known that glucocorticoids and aldosterone are able to bind glucocorticoid receptor (GR) and mineralocorticoid receptor, and these ligand-receptor interactions are redundant. It, therefore, has been impossible to delineate how these nuclear receptors couple with corticosteroid ligands and differentially regulate gene expression for operation of their distinct functions in the heart. Here, to particularly define the role of GR in cardiac muscle cells, we applied a ligand-based approach involving the GR-specific agonist cortivazol (CVZ) and the GR antagonist RU-486 and performed microarray analysis using rat neonatal cardiomyocytes. We indicated that glucocorticoids appear to be a major determinant of GR-mediated gene expression when compared with aldosterone. Moreover, expression profiles of these genes highlighted numerous roles of glucocorticoids in various aspects of cardiac physiology. At first, we identified that glucocorticoids, via GR, induce mRNA and protein expression of a transcription factor Kruppel-like factor 15 and its downstream target genes, including branched-chain aminotransferase 2, a key enzyme for amino acid catabolism in the muscle. CVZ treatment or overexpression of KLF15 decreased cellular branched-chain amino acid concentrations and introduction of small-interfering RNA against KLF15 cancelled these CVZ actions in cardiomyocytes. Second, glucocorticoid-GR signaling promoted gene expression of the enzymes involved in the prostaglandin biosynthesis, including cyclooxygenase-2 and phospholipase A2 in cardiomyocytes. Together, we may conclude that GR signaling should have distinct roles for maintenance of cardiac function, for example, in amino acid catabolism and prostaglandin biosynthesis in the heart.

    DOI: 10.1152/ajpendo.90767.2008

  • Orengedokuto and berberine improve indomethacin-induced small intestinal injury via adenosine 査読

    Yoko Watanabe-Fukuda, Masahiro Yamamoto, Naoko Miura, Masato Fukutake, Atsushi Ishige, Rui Yamaguchi, Masao Nagasaki, Ayumu Saito, Seiya Imoto, Satoru Miyano, Junzo Takeda, Kenji Watanabe

    JOURNAL OF GASTROENTEROLOGY   44 ( 5 )   380 - 389   2009年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recent endoscopic technology has revealed that small intestinal injury is a serious threat to patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs). We previously showed that Japanese herbal medicine, Orengedokuto (OGT; Huang-Lian-Jie-Du-Tang in Chinese), protects mice from lethal indomethacin (IND)-induced enteropathy. To elucidate the mechanism of the protective effect of OGT, we performed microarray analyses and high power statistical analyses of microarray data using new bioinformatics tools.
    Female BALB/c mice were subcutaneously injected with IND (20 mg/kg) once a day for 2 days. OGT-treated mice received a diet containing OGT from the first IND injection until the end of the experiment. Gene expression signals of small intestine were obtained with GeneChip(A (R)). Analyses for overrepresentation of Gene Ontology categories were conducted using MetaGene Profiler (MGP) and the changes were visualized by Cell Illustrator Online (CIO). Furthermore, active ingredients of OGT were investigated.
    MGP and CIO suggested a critical role for the adenosine system, especially adenosine deaminase (ADA), a key enzyme of adenosine catabolism. Quantitative real time RT-PCR and in situ hybridization showed that OGT decreased the expression of ADA, which possibly resulted in the elevation of the anti-inflammatory nucleoside adenosine. Blockade of the adenosine A2a receptor abrogated the protective effect of OGT. Berberine, a major ingredient of OGT, suppressed ADA expression and reduced the incidence of lethality.
    OGT may prevent IND-induced enteropathy by decreasing ADA which results in the elevation of adenosine. Modulation of the adenosine system may be an efficient therapeutic strategy for NSAID-induced enteropathy.

    DOI: 10.1007/s00535-009-0005-2

  • Analysis of PPARα-dependent and PPARα-independent transcript regulation following fenofibrate treatment of human endothelial cells 査読

    Hiromitsu Araki, Yoshinori Tamada, Seiya Imoto, Ben Dunmore, Deborah Sanders, Sally Humphrey, Masao Nagasaki, Atsushi Doi, Yukiko Nakanishi, Kaori Yasuda, Yuki Tomiyasu, Kousuke Tashiro, Cristin Print, D. Stephen Charnock-Jones, Satoru Kuhara, Satoru Miyano

    Angiogenesis   12 ( 3 )   221 - 229   2009年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s10456-009-9142-8

  • Simulation-based model checking approach to cell fate specification during Caenorhabditis elegans vulval development by hybrid functional Petri net with extension 査読

    Chen Li, Masao Nagasaki, Kazuko Ueno, Satoru Miyano

    BMC SYSTEMS BIOLOGY   3   42 - 42   2009年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Model checking approaches were applied to biological pathway validations around 2003. Recently, Fisher et al. have proved the importance of model checking approach by inferring new regulation of signaling crosstalk in C. elegans and confirming the regulation with biological experiments. They took a discrete and state-based approach to explore all possible states of the system underlying vulval precursor cell (VPC) fate specification for desired properties. However, since both discrete and continuous features appear to be an indispensable part of biological processes, it is more appropriate to use quantitative models to capture the dynamics of biological systems. Our key motivation of this paper is to establish a quantitative methodology to model and analyze in silico models incorporating the use of model checking approach.
    Results: A novel method of modeling and simulating biological systems with the use of model checking approach is proposed based on hybrid functional Petri net with extension (HFPNe) as the framework dealing with both discrete and continuous events. Firstly, we construct a quantitative VPC fate model with 1761 components by using HFPNe. Secondly, we employ two major biological fate determination rules - Rule I and Rule II - to VPC fate model. We then conduct 10,000 simulations for each of 48 sets of different genotypes, investigate variations of cell fate patterns under each genotype, and validate the two rules by comparing three simulation targets consisting of fate patterns obtained from in silico and in vivo experiments. In particular, an evaluation was successfully done by using our VPC fate model to investigate one target derived from biological experiments involving hybrid lineage observations. However, the understandings of hybrid lineages are hard to make on a discrete model because the hybrid lineage occurs when the system comes close to certain thresholds as discussed by Sternberg and Horvitz in 1986. Our simulation results suggest that: Rule I that cannot be applied with qualitative based model checking, is more reasonable than Rule II owing to the high coverage of predicted fate patterns (except for the genotype of lin-15ko; lin-12ko double mutants). More insights are also suggested.
    Conclusion: The quantitative simulation-based model checking approach is a useful means to provide us valuable biological insights and better understandings of biological systems and observation data that may be hard to capture with the qualitative one.

    DOI: 10.1186/1752-0509-3-42

  • Recursive regularization for inferring gene networks from time-course gene expression profiles 査読

    Teppei Shimamura, Seiya Imoto, Rui Yamaguchi, Andre Fujita, Masao Nagasaki, Satoru Miyano

    BMC SYSTEMS BIOLOGY   3   41 - 41   2009年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Inferring gene networks from time-course microarray experiments with vector autoregressive (VAR) model is the process of identifying functional associations between genes through multivariate time series. This problem can be cast as a variable selection problem in Statistics. One of the promising methods for variable selection is the elastic net proposed by Zou and Hastie (2005). However, VAR modeling with the elastic net succeeds in increasing the number of true positives while it also results in increasing the number of false positives.
    Results: By incorporating relative importance of the VAR coefficients into the elastic net, we propose a new class of regularization, called recursive elastic net, to increase the capability of the elastic net and estimate gene networks based on the VAR model. The recursive elastic net can reduce the number of false positives gradually by updating the importance. Numerical simulations and comparisons demonstrate that the proposed method succeeds in reducing the number of false positives drastically while keeping the high number of true positives in the network inference and achieves two or more times higher true discovery rate (the proportion of true positives among the selected edges) than the competing methods even when the number of time points is small. We also compared our method with various reverse-engineering algorithms on experimental data of MCF-7 breast cancer cells stimulated with two ErbB ligands, EGF and HRG.
    Conclusion: The recursive elastic net is a powerful tool for inferring gene networks from time-course gene expression profiles.

    DOI: 10.1186/1752-0509-3-41

  • BFL: a node and edge betweenness based fast layout algorithm for large scale networks 査読

    Tatsunori B. Hashimoto, Masao Nagasaki, Kaname Kojima, Satoru Miyano

    BMC BIOINFORMATICS   10   19 - 19   2009年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Network visualization would serve as a useful first step for analysis. However, current graph layout algorithms for biological pathways are insensitive to biologically important information, e. g. subcellular localization, biological node and graph attributes, or/and not available for large scale networks, e. g. more than 10000 elements.
    Results: To overcome these problems, we propose the use of a biologically important graph metric, betweenness, a measure of network flow. This metric is highly correlated with many biological phenomena such as lethality and clusters. We devise a new fast parallel algorithm calculating betweenness to minimize the preprocessing cost. Using this metric, we also invent a node and edge betweenness based fast layout algorithm (BFL). BFL places the high-betweenness nodes to optimal positions and allows the low-betweenness nodes to reach suboptimal positions. Furthermore, BFL reduces the runtime by combining a sequential insertion algorim with betweenness. For a graph with n nodes, this approach reduces the expected runtime of the algorithm to O(n(2)) when considering edge crossings, and to O(n log n) when considering only density and edge lengths.
    Conclusion: Our BFL algorithm is compared against fast graph layout algorithms and approaches requiring intensive optimizations. For gene networks, we show that our algorithm is faster than all layout algorithms tested while providing readability on par with intensive optimization algorithms. We achieve a 1.4 second runtime for a graph with 4000 nodes and 12000 edges on a standard desktop computer.

    DOI: 10.1186/1471-2105-10-19

  • Bayesian learning of biological pathways on genomic data assimilation 査読

    Ryo Yoshida, Masao Nagasaki, Rui Yamaguchi, Seiya Imoto, Satoru Miyano, Tomoyuki Higuchi

    BIOINFORMATICS   24 ( 22 )   2592 - 2601   2008年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Motivation: Mathematical modeling and simulation, based on biochemical rate equations, provide us a rigorous tool for unraveling complex mechanisms of biological pathways. To proceed to simulation experiments, it is an essential. first step to. find effective values of model parameters, which are difficult to measure from in vivo and in vitro experiments. Furthermore, once a set of hypothetical models has been created, any statistical criterion is needed to test the ability of the constructed models and to proceed to model revision.
    Results: The aim of our research is to present a new statistical technology towards data-driven construction of in silico biological pathways. The method starts with a knowledge-based modeling with hybrid functional Petri net. It then proceeds to the Bayesian learning of model parameters for which experimental data are available. This process exploits quantitative measurements of evolving biochemical reactions, e. g. gene expression data. Another important issue that we consider is statistical evaluation and comparison of the constructed hypothetical pathways. For this purpose, we have developed a new Bayesian information-theoretic measure that assesses the predictability and the biological robustness of in silico pathways.

    DOI: 10.1093/bioinformatics/btn483

  • ExonMiner: Web service for analysis of GeneChip Exon array data 査読

    Kazuyuki Numata, Ryo Yoshida, Masao Nagasaki, Ayumu Saito, Seiya Imoto, Satoru Miyano

    BMC BIOINFORMATICS   9   494 - 494   2008年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Some splicing isoform-specific transcriptional regulations are related to disease. Therefore, detection of disease specific splice variations is the first step for finding disease specific transcriptional regulations. Affymetrix Human Exon 1.0 ST Array can measure exon-level expression profiles that are suitable to find differentially expressed exons in genome-wide scale. However, exon array produces massive datasets that are more than we can handle and analyze on personal computer.
    Results: We have developed ExonMiner that is the first all-in-one web service for analysis of exon array data to detect transcripts that have significantly different splicing patterns in two cells, e. g. normal and cancer cells. ExonMiner can perform the following analyses: (1) data normalization, (2) statistical analysis based on two-way ANOVA, (3) finding transcripts with significantly different splice patterns, (4) efficient visualization based on heatmaps and barplots, and (5) meta-analysis to detect exon level biomarkers. We implemented ExonMiner on a supercomputer system in order to perform genome-wide analysis for more than 300,000 transcripts in exon array data, which has the potential to reveal the aberrant splice variations in cancer cells as exon level biomarkers.
    Conclusion: ExonMiner is well suited for analysis of exon array data and does not require any installation of software except for internet browsers. What all users need to do is to access the ExonMiner URL http://ae.hgc.jp/exonminer. Users can analyze full dataset of exon array data within hours by high-level statistical analysis with sound theoretical basis that finds aberrant splice variants as biomarkers.

    DOI: 10.1186/1471-2105-9-494

  • Fast grid layout algorithm for biological networks with sweep calculation 査読

    Kaname Kojima, Masao Nagasaki, Satoru Miyano

    BIOINFORMATICS   24 ( 12 )   1433 - 1441   2008年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Motivation: Properly drawn biological networks are of great help in the comprehension of their characteristics. The quality of the layouts for retrieved biological networks is critical for pathway databases. However, since it is unrealistic to manually draw biological networks for every retrieval, automatic drawing algorithms are essential. Grid layout algorithms handle various biological properties such as aligning vertices having the same attributes and complicated positional constraints according to their subcellular localizations; thus, they succeed in providing biologically comprehensible layouts. However, existing grid layout algorithms are not suitable for real-time drawing, which is one of requisites for applications to pathway databases, due to their high-computational cost. In addition, they do not consider edge directions and their resulting layouts lack traceability for biochemical reactions and gene regulations, which are the most important features in biological networks.
    Results: We devise a new calculation method termed sweep calculation and reduce the time complexity of the current grid layout algorithms through its encoding and decoding processes. We conduct practical experiments by using 95 pathway models of various sizes from TRANSPATH and show that our new grid layout algorithm is much faster than existing grid layout algorithms. For the cost function, we introduce a new component that penalizes undesirable edge directions to avoid the lack of traceability in pathways due to the differences in direction between in-edges and out-edges of each vertex.

    DOI: 10.1093/bioinformatics/btn196

  • Systematic reconstruction of TRANSPATH data into Cell System Markup Language 査読

    Masao Nagasaki, Ayumu Saito, Chen Li, Euna Jeong, Satoru Miyano

    BMC SYSTEMS BIOLOGY   2   53 - 53   2008年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Many biological repositories store information based on experimental study of the biological processes within a cell, such as protein-protein interactions, metabolic pathways, signal transduction pathways, or regulations of transcription factors and miRNA. Unfortunately, it is difficult to directly use such information when generating simulation-based models. Thus, modeling rules for encoding biological knowledge into system-dynamics-oriented standardized formats would be very useful for fully understanding cellular dynamics at the system level.
    Results: We selected the TRANSPATH database, a manually curated high-quality pathway database, which provides a plentiful source of cellular events in humans, mice, and rats, collected from over 31,500 publications. In this work, we have developed 16 modeling rules based on hybrid functional Petri net with extension (HFPNe), which is suitable for graphical representing and simulating biological processes. In the modeling rules, each Petri net element is incorporated with Cell System Ontology to enable semantic interoperability of models. As a formal ontology for biological pathway modeling with dynamics, CSO also defines biological terminology and corresponding icons. By combining HFPNe with the CSO features, it is possible to make TRANSPATH data to simulation-based and semantically valid models. The results are encoded into a biological pathway format, Cell System Markup Language (CSML), which eases the exchange and integration of biological data and models.
    Conclusion: By using the 16 modeling rules, 97% of the reactions in TRANSPATH are converted into simulation-based models represented in CSML. This reconstruction demonstrates that it is possible to use our rules to generate quantitative models from static pathway descriptions.

    DOI: 10.1186/1752-0509-2-53

  • An efficient grid layout algorithm for biological networks utilizing various biological attributes 査読

    Kaname Kojima, Masao Nagasaki, Euna Jeong, Mitsuru Kato, Satoru Miyano

    BMC BIOINFORMATICS   8   76 - 76   2007年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Clearly visualized biopathways provide a great help in understanding biological systems. However, manual drawing of large-scale biopathways is time consuming. We proposed a grid layout algorithm that can handle gene-regulatory networks and signal transduction pathways by considering edge-edge crossing, node-edge crossing, distance measure between nodes, and subcellular localization information from Gene Ontology. Consequently, the layout algorithm succeeded in drastically reducing these crossings in the apoptosis model. However, for larger-scale networks, we encountered three problems: (i) the initial layout is often very far from any local optimum because nodes are initially placed at random, (ii) from a biological viewpoint, human layouts still exceed automatic layouts in understanding because except subcellular localization, it does not fully utilize biological information of pathways, and (iii) it employs a local search strategy in which the neighborhood is obtained by moving one node at each step, and automatic layouts suggest that simultaneous movements of multiple nodes are necessary for better layouts, while such extension may face worsening the time complexity.
    Results: We propose a new grid layout algorithm. To address problem (i), we devised a new force-directed algorithm whose output is suitable as the initial layout. For (ii), we considered that an appropriate alignment of nodes having the same biological attribute is one of the most important factors of the comprehension, and we defined a new score function that gives an advantage to such configurations. For solving problem (iii), we developed a search strategy that considers swapping nodes as well as moving a node, while keeping the order of the time complexity. Though a nave implementation increases by one order, the time complexity, we solved this difficulty by devising a method that caches differences between scores of a layout and its possible updates.
    Conclusion: Layouts of the new grid layout algorithm are compared with that of the previous algorithm and human layout in an endothelial cell model, three times as large as the apoptosis model. The total cost of the result from the new grid layout algorithm is similar to that of the human layout. In addition, its convergence time is drastically reduced (40% reduction).

    DOI: 10.1186/1471-2105-8-76

  • AYUMS: an algorithm for completely automatic quantitation based on LC-MS/MS proteome data and its application to the analysis of signal transduction 査読

    Ayumu Saito, Masao Nagasaki, Masaaki Oyama, Hiroko Kozuka-Hata, Kentaro Semba, Sumio Sugano, Tadashi Yamamoto, Satoru Miyano

    BMC BIOINFORMATICS   8   15 - 15   2007年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Comprehensive description of the behavior of cellular components in a quantitative manner is essential for systematic understanding of biological events. Recent LC-MS/MS (tandem mass spectrometry coupled with liquid chromatography) technology, in combination with the SILAC (Stable Isotope Labeling by Amino acids in Cell culture) method, has enabled us to make relative quantitation at the proteome level. The recent report by Blagoev et al. (Nat. Biotechnol., 22, 1139-1145, 2004) indicated that this method was also applicable for the time-course analysis of cellular signaling events. Relative quatitation can easily be performed by calculating the ratio of peak intensities corresponding to differentially labeled peptides in the MS spectrum. As currently available software requires some GUI applications and is time-consuming, it is not suitable for processing large-scale proteome data.
    Results: To resolve this difficulty, we developed an algorithm that automatically detects the peaks in each spectrum. Using this algorithm, we developed a software tool named AYUMS that automatically identifies the peaks corresponding to differentially labeled peptides, compares these peaks, calculates each of the peak ratios in mixed samples, and integrates them into one data sheet. This software has enabled us to dramatically save time for generation of the final report.
    Conclusion: AYUMS is a useful software tool for comprehensive quantitation of the proteome data generated by LC-MS/MS analysis. This software was developed using Java and runs on Linux, Windows, and Mac OSX.

    DOI: 10.1186/1741-2105-8-15

  • Simulation-based validation of the p53 transcriptional activity with hybrid functional Petri net 査読

    Atsushi Doi, Masao Nagasaki, Hiroshi Matsuno, Satoru Miyano

    In Silico Biology   6 ( 1-2 )   1 - 13   2006年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    MDM2 and p19ARF are essential proteins in cancer pathways forming a complex with protein p53 to control the transcriptional activity of protein p53. It is confirmed that protein p53 loses its transcriptional activity by forming the functional dimer with protein MDM2. However, it is still unclear that protein p53 keeps its transcriptional activity when it forms the trimer with proteins MDM2 and p19ARF. We have observed mutual behaviors among genes p53, MDM2, p19ARF and their products on a computational model with hybrid functional Petri net (HFPN) which is constructed based on information described in the literature. The simulation results suggested that protein p53 should have the transcriptional activity in the forms of the trimer of proteins p53, MDM2, and p19ARF. This paper also discusses the advantages of HFPN based modeling method in terms of pathway description for simulations. © 2006 IOS Press. All rights reserved.

  • [Dynamic pathway modeling language: CSML]. 査読

    Nagasaki M, Doi A, Miyano S

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme   50 ( 16 Suppl )   2269 - 2274   2005年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    [Dynamic pathway modeling language: CSML].

▼全件表示

書籍等出版物

  • 遺伝学の百科事典

    公益財団法人 遺伝学普及会 日本遺伝学会 編(範囲:Pp198)

    丸善出版  2022年1月 

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  • 遺伝子医学36号,特集:Common disease解析の最前線

    Gervais Olivier, 河合 洋介, 長﨑 正朗

    メディカルドゥ  2021年4月 

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    記述言語:その他  

  • ジャポニカアレイの設計と全ゲノムインピュテーションによる活用

    河合洋介, 三森隆広, 小島要, 成相直樹, 長﨑正朗(担当:共著)

    月刊メディカル・サイエンス・ダイジェスト  2015年5月 

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    記述言語:その他  

    ジャポニカアレイの設計と全ゲノムインピュテーションによる活用

講演・口頭発表等

  • Genome-wide Meta and Gene Ontology Analysis for High Myopia

    Kazuya Morino, Masahiro Miyake, Akira Meguro, Masao Nagasaki, Yuki Mori, Shin-ya Nakao, Takuro Kamei, Nao Aisu, Akitaka Tsujikawa

    American Academy of Ophthalmology 2023  2023年11月 

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    開催年月日: 2023年11月

    記述言語:日本語  

    開催地:Moscone Center, San Francisco   国名:日本国  

  • 抗原提示補助シグナル分子の遺伝的バリアントに起因する自己免疫疾患感受性の分子機序の解明

    人見 祐基、植野 和子、相葉 佳洋、西田 奈央、河合 洋介、川嶋 実苗、 Seik-Soon Khor、長崎 正朗、徳永 勝士、中村 稔

    第31回日本組織適合性学会大会  2023年9月 

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    開催年月日: 2023年9月

    記述言語:日本語  

    開催地:一橋大学学術総合センター   国名:日本国  

  • 未来医療へのヒト情報解析基盤構築と実装

    長﨑 正朗

    未来社会デザイン統括本部&データ駆動イノベーション推進本部 合同シンポジウム2023  2023年9月 

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    開催年月日: 2023年9月

    記述言語:日本語  

    開催地:九州大学伊都キャンパス椎木講堂   国名:日本国  

  • ヒトゲノム情報や臨床情報のセキュリティと情報解析の取り組みについて

    長﨑 正朗

    αxSC2023Q セキュリティとスーパーコンピュータシンポジウム  2023年7月 

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    開催年月日: 2023年7月

    記述言語:日本語  

    開催地:九州大学情報基盤研究開発センター   国名:日本国  

  • ヒトゲノムと臨床情報の統合解析に向けたハイブリッドクラウド基盤構築とパブリッククラウドの活用

    長﨑 正朗

    教育と研究のDXフォーラム  2023年7月 

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    開催年月日: 2023年7月

    記述言語:日本語  

    開催地:福岡会場 西南学院大学 コミュニティセンター   国名:日本国  

  • ハイブリッドクラウドを用いたゲノム情報に基づく構造多型パネルの構築とアノテーション(口頭発表)

    長﨑 正朗

    学際大規模情報基盤共同利用・共同研究拠点 第 15回シンポジウム  2023年7月 

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    開催年月日: 2023年7月

    記述言語:日本語  

    開催地:オンライン(Tokyo)   国名:日本国  

  • 難病レジストリ研究の運用構築支援とデータシェアリング推進(難病プラットフォーム活動報告)

    Izumi Yamaguchi, Naoko Yagishita, Kazumasa Tanzawa, Yoshihiko Furusawa, Masao Nagasaki, Yoshihisa Yamano, Fumihiko Matsuda

    第27回日本医療情報学会春季学術大会  2023年6月 

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    開催年月日: 2023年6月 - 2023年7月

    記述言語:日本語  

    開催地:沖縄コンベンションセンター   国名:日本国  

  • 自己免疫疾患感受性遺伝子に起因する発症機序の解明におけるCRISPR/Cas9の活用 Utilization of CRISPR/Cas9 to elucidate the pathogenesis of autoimmune disease-susceptibility genes

    人見 祐基, 植野 和子, 相葉 佳洋, 西田 奈央, 河合 洋介, 川嶋 実苗, Khor Seik-Soon, 長﨑 正朗, 徳永 勝士, 中村 稔 Yuki Hitomi, Kazuko Ueno, Yoshihiro Aiba, Nao Nishida, Yosuke Kawai, Minae Kawashima, Seik-Soon Khor, Masao Nagasaki, Katsushi Tokunaga, Minoru Nakamura

    日本ゲノム編集学会 第8回大会 8th Annual Meeting of The Japanese Society for Genome Editing  2023年6月 

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    開催年月日: 2023年6月

    記述言語:日本語  

    開催地:タワーホール船堀   国名:日本国  

  • ハイブリッドクラウド構築とゲノム情報解析の効率的な運用に関した研究

    長﨑正朗

    学際大規模情報基盤共同利用・共同研究拠点 第 13 回シンポジウム  2021年7月 

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    開催年月日: 2021年7月

    記述言語:日本語  

    国名:その他  

    ハイブリッドクラウド構築とゲノム情報解析の効率的な運用に関した研究

  • 尿酸値の失われた遺伝率は、 レアバリアントがかなりの部分を説明する

    三澤 計治, 長谷川 嵩矩, 三島 英換, Promsuk Jutabha, 大内 基司, 小島 要, 河合 洋介, 松尾 雅文, 安西 尚彦, 長崎 正朗

    日本バイオインフォマティクス学会  2020年9月 

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    開催年月日: 2020年9月

    記述言語:日本語  

    国名:その他  

    尿酸値の失われた遺伝率は、 レアバリアントがかなりの部分を説明する

  • ゲノム医科学における国内外のヒトゲノム解析の状況 およびハイブリッドクラウド計算環境の構築と活用

    長﨑 正朗

    第44回日本分子生物学会年会  2021年12月 

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    記述言語:日本語  

    国名:その他  

    Large-Scale Human Genome Analysis in Genomic Medicine and Utilization of Hybrid Cloud Computing System

  • 日本人の公開可能な長鎖型集団パネル構築とその意義について

    長﨑 正朗

    PacBio ユーザーグループミーティング 2022  2022年5月 

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    記述言語:日本語  

    国名:その他  

  • ハイブリッドクラウド構築とゲノム情報解析の効率的な運用に関した研究

    長﨑正朗

    学際大規模情報基盤共同利用・共同研究拠点 第 14回シンポジウム  2022年7月 

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    記述言語:日本語  

    国名:その他  

  • 日本人集団における原発性胆汁性胆管炎の感受性、病期分類、症候学的状態、自己免疫性肝炎、肝細胞癌の発症と新規HLA対立遺伝子との関連性(Novel HLA allele associations with susceptibility, staging, symptomatic state, autoimmune hepatitis and hepatocellular carcinoma events for primary biliary cholangitis in the Japanese population)

    Khor Seik-Soon, Ueno Kazuko, Nishida Nao, Kawashima Minae, Kawai Yosuke, Aiba Yoshihiro, Hitomi Yuki, Nagasaki Masao, Nakamura Minoru, Tokunaga Katsushi

    MHC: Major Histocompatibility Complex  2023年8月  (一社)日本組織適合性学会

     詳細を見る

    記述言語:英語  

  • 日本人の公開可能な長鎖型集団パネル構築とその意義について

    長﨑 正朗

    PacBio ユーザーグループミーティング 2022  2022年5月 

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    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    researchmap

  • ロングリードシーケンス技術による新規融合遺伝子LILRB3-LILRB5の同定と特徴(Identification and characterization of the novel fusion gene LILRB3-LILRB5 by long-read sequencing technology)

    Hirayasu Kouyuki, Khor Seik-Soon, Kawai Yosuke, Hasegawa Gen, Tokunaga Katsushi, Hanayama Rikinari, Nagasaki Masao

    日本免疫学会総会・学術集会記録  2023年12月  (NPO)日本免疫学会

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    記述言語:英語  

  • ハイブリッドクラウド構築とゲノム情報解析の効率的な運用に関した研究

    長﨑正朗

    学際大規模情報基盤共同利用・共同研究拠点 第 14回シンポジウム  2022年7月 

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    記述言語:日本語   会議種別:口頭発表(一般)  

    researchmap

▼全件表示

MISC

  • 様々な免疫形質と関連するCD28領域におけるスプライシング制御バリアントの同定

    人見祐基, 相葉佳洋, 植野和子, 西田奈央, 河合洋介, 川嶋実苗, 築地信, 岩渕千里, 高田紗奈美, 三宅紀子, 長崎正朗, 徳永勝士, 中村稔, 中村稔

    日本人類遺伝学会大会プログラム・抄録集   67th (CD-ROM)   2022年

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  • 原発性胆汁性胆管炎(PBC)感受性遺伝子領域を対象とした機能的遺伝子多型(causal variant)の同定

    人見 祐基, 河合 洋介, 植野 和子, 西田 奈央, 川嶋 実苗, 相葉 佳洋, 築地 信, 長崎 正朗, 中村 稔, 徳永 勝士

    MHC: Major Histocompatibility Complex   2019年9月

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    記述言語:日本語  

  • Longitudinal Analysis of Relationships between Individual Fatty Acids and Gestational Diabetes Mellitus in Maternity Log Study.

    Satsuki Kumatani, Ochi Daisuke, Yamauchi Takafumi, Tsunemoto Yoshiki, Wagata Maiko, Tanabe Osamu, Minegishi Naoko, Hiyama Satoshi, Nagasaki Masao, Sugawara Junichi

    REPRODUCTIVE SCIENCES   2019年3月

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    記述言語:英語  

  • Correlation Network Analysis of Maternal Lifelogs and Plasma Metabolites in Maternity Log Study.

    Takafumi Yamauchi, Daisuke Ochi, Takahiro Mimori, Yoshiki Tsunemoto, Satsuki Kumatani, Maiko Wagata, Riu Yamashita, Osamu Tanabe, Naoko Minegishi, Nobuo Yaegashi, Satoshi Hiyama, Masao Nagasaki, Junichi Sugawara

    REPRODUCTIVE SCIENCES   2019年3月

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    記述言語:英語  

  • GWAS and RNA Expression Analysis for Gestational Hypertension using Time-Series Home Blood Pressure Data in Maternity Log Study.

    Yoshiki Tsunemoto, Takafumi Yamauchi, Daisuke Ochi, Satsuki Kumatani, Takahiro Mimori, Kaname Kojima, Riu Yamashita, Maiko Wagata, Fumiki Katsuoka, Osamu Tanabe, Naoko Minegishi, Satoshi Hiyama, Masao Nagasaki, Junichi Sugawara

    REPRODUCTIVE SCIENCES   2019年3月

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    記述言語:英語  

  • Estimating frequency of pathogenic variants in a Japanese population by using the whole-genome reference panel of ToMMo

    Yumi Yamaguchi-Kabata, Jun Yasuda, Osamu Tanabe, Yoichi Suzuki, Hiroshi Kawame, Nobuo Fuse, Masao Nagasaki, Yosuke Kawai, Kaname Kojima, Fumiki Katsuoka, Sakae Saito, Inaho Danjoh, Ikuko N. Motoike, Riu Yamashita, Seizo Koshiba, Daisuke Saigusa, Gen Tamiya, Shigeo Kure, Nobuo Yaegashi, Yoshio Kawaguchi, Fuji Nagami, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Atsushi Hozawa, Soichi Ogishima, Hideyasu Kiyomoto, Takako Takai-Igarashi, Kengo Kinoshita, Masayuki Yamamoto

    HUMAN GENOMICS   2018年3月

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    記述言語:英語  

  • 妊娠高血圧症候群の発症予測に向けた時系列ライフログ解析

    山内 隆史, 越智 大介, 恒元 淑希, 和形 麻衣子, 原田 祐希, 山下 理宇, 田邉 修, 八重樫 伸生, 檜山 聡, 長崎 正朗, 菅原 準一

    日本妊娠高血圧学会雑誌   2017年9月

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    記述言語:日本語  

    妊娠高血圧症候群の発症予測に向けた時系列ライフログ解析

  • 卵巣明細胞がんを引き起こす遺伝子変異の発見(Discovery of gene alterations causing ovarian clear cell carcinoma)

    Shibuya Yusuke, Tokunaga Hideki, Saito Sakae, Kojima Kaname, Li Bin, Nagasaki Masao, Yasuda Jun, Yaegashi Nobuo

    日本婦人科腫瘍学会雑誌   2017年6月

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    記述言語:英語  

  • プライバシ保護ゲノム解析のための秘密計算フィッシャー正確検定の実装評価

    長谷川 聡, 濱田 浩気, 三澤 計治, 千田 浩司, 荻島 創一, 長﨑 正朗

    マルチメディア,分散協調とモバイルシンポジウム2017論文集   2017年6月

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    記述言語:日本語  

  • プライバシ保護ゲノム解析のための秘密計算フィッシャー正確検定の実装評価

    長谷川聡, 濱田浩気, 三澤計治, 三澤計治, 千田浩司, 荻島創一, 荻島創一, 長崎正朗, 長崎正朗

    情報処理学会シンポジウムシリーズ(CD-ROM)   2017年6月

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    記述言語:日本語  

    プライバシ保護ゲノム解析のための秘密計算フィッシャー正確検定の実装評価

  • Physical Activity and Periodontal Bacteria in Saliva among Japanese Adults

    Cong Huang, Riu Yamashita, Yukuto Sato, Haruki Momma, Junko Kawashima, Bin Ye, Shota Sugiyama, Masakazu Nanno, Akito Tsuboi, Masao Nagasaki, Ryoichi Nagatomi

    MEDICINE AND SCIENCE IN SPORTS AND EXERCISE   2017年5月

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    記述言語:英語  

    DOI: 10.1249/01.mss.0000519107.55215.92

  • Genome-wide association study identifies novel susceptibility loci for tanning ability in Japanese population

    K. Shido, K. Kojima, A. Hozawa, S. Ogishima, N. Minegishi, Y. Kawai, G. Tamiya, K. Tanno, K. Yamasaki, S. Aiba, Y. Suzuki, M. Nagasaki

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   2017年5月

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    記述言語:英語  

  • POPULATION-OPTIMIZED SNP ARRAY REVEALS RAP1A AS A NOVEL CANDIDATE SUSCEPTIBILITY GENE FOR CROHN'S DISEASE IN JAPANESE INDIVIDUALS

    Yoichi Kakuta, Yosuke Kawai, Takeo Naito, Atsushi Hirano, Junji Umeno, Keiichiro Hiramoto, Masatake Kuroha, Yoshitake Kanazawa, Tomoya Kimura, Katsuya Endo, Yoshitaka Kinouchi, Motohiro Esaki, Masao Nagasaki, Tooru Shimosegawa

    GASTROENTEROLOGY   2017年4月

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    記述言語:英語  

  • DICHOTOMOUS EFFECTS OF ATG16L1 AND LRRK2 IN MODULATING PANETH CELL DEFECT IN JAPANESE AND NORTH AMERICAN CROHN'S DISEASE PATIENTS

    Ta-Chiang Liu, Takeo Naito, Zhenqiu Liu, Kelli VanDussen, Talin Haritunians, Dalin Li, Katsuya Endo, Yosuke Kawai, Masao Nagasaki, Yoshitaka Kinouchi, Dermot McGovern, Tooru Shimosegawa, Yoichi Kakuta, Thaddeus S. Stappenbeck

    GASTROENTEROLOGY   2017年4月

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    記述言語:英語  

  • 早発型発達緑内障における原因遺伝子の探索

    布施 昇男, 木村 雅恵, 清水 愛, 河合 洋介, 小島 要, 長崎 正朗, 濱中 輝彦, 石田 誠夫, 中村 誠, 酒井 寛, 池田 陽子, 森 和彦, 中澤 徹, 勝岡 史城, 安田 純, 山本 雅之

    日本眼科学会雑誌   2017年3月

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    記述言語:日本語  

  • Identification of Somatic Genetic Alterations in Ovarian Clear Cell Carcinomas with Next Generation Sequencing.

    Yusuke Shibuya, Sakae Saito, Kaname Kojima, Bin Li, Hideki Tokunaga, Masao Nagasaki, Jun Yasuda, Nobuo Yaegashi

    REPRODUCTIVE SCIENCES   2017年3月

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    記述言語:英語  

  • 次世代シークエンサーを用いた卵巣明細胞腺癌の遺伝子変異の探索

    渋谷 祐介, 齋藤 さかえ, 小島 要, 李 賓, 徳永 英樹, 長崎 正朗, 安田 純, 八重樫 伸生

    日本癌学会総会記事   2016年10月

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    記述言語:英語  

    次世代シークエンサーを用いた卵巣明細胞腺癌の遺伝子変異の探索

  • マルチオミクスが解き明かす疾患生物学 日本人多層オミックス参照パネルの拡張

    小柴 生造, 三枝 大輔, 元池 育子, 小島 要, 城田 松之, 齋藤 智, 勝岡 史城, 河合 洋介, 山口 由美, 田邉 修, 長崎 正郎, 安田 純, 木下 賢吾, 山本 雅之

    日本生化学会大会プログラム・講演要旨集   2016年9月

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    記述言語:日本語  

    マルチオミクスが解き明かす疾患生物学 日本人多層オミックス参照パネルの拡張

  • 秘密計算フィッシャー正確検定(1)標本数が少ない場合 (情報セキュリティ)

    千田 浩司, 長谷川 聡, 濱田 浩気, 荻島 創一, 三澤 計治, 長﨑 正朗

    電子情報通信学会技術研究報告 = IEICE technical report : 信学技報   2016年7月

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    記述言語:日本語  

    Privacy Preserving Fisher's Exact Test(1)For Small Samples

  • プライバシ保護ゲノム解析のための秘密計算フィッシャー正確検定 (情報セキュリティ)

    長谷川 聡, 濱田 浩気, 千田 浩司, 荻島 創一, 三澤 計治, 長﨑 正朗

    電子情報通信学会技術研究報告 = IEICE technical report : 信学技報   2016年7月

     詳細を見る

    記述言語:日本語  

    Privacy Preserving Fisher's Exact Test for GWAS

  • 秘密計算フィッシャー正確検定(2)標本数が多い場合 (情報セキュリティ)

    濱田 浩気, 長谷川 聡, 千田 浩司, 荻島 創一, 三澤 計治, 長崎 正朗

    電子情報通信学会技術研究報告 = IEICE technical report : 信学技報   2016年7月

     詳細を見る

    記述言語:日本語  

    Privacy Preserving Fisher's Exact Test(2)For Large Samples

  • 卵巣明細胞腺癌を引き起こす遺伝子変異の発見(Discovery of gene alterations causing ovarian clear cell carcinoma)

    渋谷 祐介, 徳永 英樹, 安田 純, 長崎 正朗, 斎藤 さかえ, 小島 要, 李 賓, 八重樫 伸生

    日本婦人科腫瘍学会雑誌   2016年6月

     詳細を見る

    記述言語:英語  

    卵巣明細胞腺癌を引き起こす遺伝子変異の発見(Discovery of gene alterations causing ovarian clear cell carcinoma)

  • Estimation of allele frequency of pathological variants based on whole-genome sequencing of 1070 Japanese individuals

    Yumi Yamaguchi-Kabata, Yosuke Kawai, Kaname Kojima, Naoki Nariai, Takahiro Mimori, Yukuto Sato, Fumiki Katsuoka, Jun Yasuda, Masayuki Yamamoto, Masao Nagasaki

    GENES & GENETIC SYSTEMS   2015年12月

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    記述言語:英語  

  • 日本人全ゲノムファレンスパネルの構築と今後

    長崎正朗, 安田純, 勝岡史城, 成相直樹, 小島要, 河合洋介, 山口由美, 横澤潤二, 檀上稲穂, 齊藤さかえ, 佐藤行人, 三森隆弘, 津田薫, 齊藤るみ子, PAN Xiaoquing, 西川聡, 伊藤信, 黒木陽子, 田邉修, 布施昇男, 栗山進一, 清元秀泰, 寶澤篤

    日本遺伝学会大会プログラム・予稿集   2015年9月

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    記述言語:日本語  

    日本人全ゲノムファレンスパネルの構築と今後

  • SUGAR: graphical user interface-based high-resolution data cleaning tool for high-throughput sequencing data

    Yukuto Sato, Kaname Kojima, Naoki Nariai, Yumi Yamaguchi-Kabata, Yosuke Kawai, Masao Nagasaki

    GENES & GENETIC SYSTEMS   2014年12月

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    記述言語:英語  

  • Construction of Japanese Whole Genome Information and Data Analysis in Tohoku Medical Megabank Organization

    Masao Nagasaki

    GENES & GENETIC SYSTEMS   2014年12月

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    記述言語:英語  

  • Nonparametric inference of population demography from SNP data

    Yosuke Kawai, Yukuto Sato, Yumi Yamaguchi, Naoki Nariai, Sachiyo Sugimoto, Takahiro Mimori, Kaname Kojima, Masao Nagasaki

    GENES & GENETIC SYSTEMS   2014年12月

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    記述言語:英語  

  • 食道扁平上皮癌でのBAP1遺伝子変異によるGIS期移行異常(BAP1 mutation somatically occurring in a human esophageal squamous cell carcinoma abrogates G1-S transition)

    森 隆弘, 住井 真紀子, 斎木 由利子, 長崎 正朗, 千葉 奈津子, 石岡 千加史

    日本癌学会総会記事   2014年9月

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    記述言語:英語  

    食道扁平上皮癌でのBAP1遺伝子変異によるGIS期移行異常(BAP1 mutation somatically occurring in a human esophageal squamous cell carcinoma abrogates G1-S transition)

  • IDENTIFICATION OF ACQUIRED MUTATIONS BY WHOLE-GENOME SEQUENCING IN MONOMAC SYNDROME EVOLVING INTO MYELODYSPLASIA AND ACUTE LEUKEMIA

    T. Fujiwara, N. Fukuhara, R. Funayama, N. Nariai, M. Kamata, T. Nagashima, K. Kojima, Y. Onishi, Y. Sasahara, K. Ishizawa, M. Nagasaki, K. Nakayama, H. Harigae

    HAEMATOLOGICA   2014年6月

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    記述言語:英語  

  • 腎疾患個別化医療実現に向けた健常人ゲノムコホートの構築

    清元 秀泰, 阿部 倫昭, 奥田 拓史, 岡村 将史, 宮崎 真理子, 寳澤 篤, 栗山 進一, 高井 貴子, 長崎 正朗, 峯岸 直子, 安田 純, 森 建文, 中谷 純, 菅原 準一, 八重樫 伸生, 佐藤 博, 山本 雅之, 伊藤 貞嘉

    日本腎臓学会誌   2014年5月

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    記述言語:日本語  

    腎疾患個別化医療実現に向けた健常人ゲノムコホートの構築

  • 眼疾患と遺伝子 緑内障のゲノム解析 次世代医療・個別化医療に向けて

    布施 昇男, 清水 愛, 木村 雅恵, 高野 良真, 石 棟, 宮澤 晃子, 国松 志保, 劉 孟林, 渡邉 亮, 安田 正幸, 横山 悠, 檜森 紀子, 津田 聡, 山本 耕太郎, 中澤 徹, 安田 純, 勝岡 史城, 小島 要, 成相 直樹, 松本 光代, 元池 育子, 長崎 正朗, 木下 賢吾, 五十嵐 和彦, 山本 雅之, 新堀 哲也, 青木 洋子, 松原 洋一, 舟山 亮, 長嶋 剛史, 中山 啓子, 眞島 行彦, 船山 智代, 田中 光一, 原田 高幸, 阿部 春樹, 福地 健郎, 安田 典子, 出田 秀尚, 鄭 暁東, 白石 敦, 大橋 裕一, 石田 誠夫, 原 岳, 金森 章泰, 山田 裕子, 中村 誠, 酒井 寛, Richards Julia E

    日本眼科学会雑誌   2014年3月

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    記述言語:日本語  

    主に1990年代から始まった遺伝要因が発症に関係する疾患の解析は,単一遺伝子疾患や遺伝子変異(mutation)から多因子疾患の感受性因子である遺伝子多型(variation)へと移行してきた.個人ゲノムの解析が進むにつれて,個々人の間にはゲノム全体で数百万ヶ所の塩基配列が異なることが判明している.この塩基配列の相違が頻度の高い疾患(common disease)の発症に関わっていることが証明されてきた.近年ゲノム全体にわたる一塩基多型(single nucleotide polymorphism:SNP)を用いた相関解析(genome-wide association study:GWAS)が盛んに行われてきているが,高頻度の多型(common variant)はその病気への寄与が比較的小さいことから,臨床研究をより精度の高いものにするためには,common variantに加えて,病気への寄与度が大きい低頻度の多型(rare variant)の解析も行うことが必要である.さらにゲノム情報を用いた次世代医療,個別化医療に向け,種々の表現型(endophenotype)との関連を調べることは重要である.本研究において,我々は緑内障の病態解明をゲノム解析の観点から検討した.現在まで緑内障原因遺伝子は数種類同定されているが,当初はメンデル遺伝性の家系解析からの同定が主であった.2007年,GWASによって,LOXL1遺伝子の多型と【嚢】性緑内障が関連すると報告され,我々を含む多施設で追試された.それ以降,SNPを用いた相関解析が主流となってきており,原発開放隅角緑内障(primary open-angle glaucoma:POAG),正常眼圧緑内障(normal-tension glaucoma:NTG)に関連した遺伝子としてCDKN2B-AS1遺伝子などが発表された.また我々は,緑内障GLC1B遺伝子座が存在する常染色体2番上において,SNPを用いた相関解析により,Hexokinase 2(HK2)遺伝子多型rs678350がPOAG,NTGに関連していることを明らかにし,NCK2遺伝子多型rs2033008がNTGに関連していることを示した.マウスを用いてHk2,Nck2蛋白質の免疫組織染色を行った結果,神経節細胞に発現がみられ,緑内障の病態に関連していると考えられた.近年,遺伝子解析は,マーカーを用いた相関解析から次世代シークエンサーを用いた網羅的な解析へと移行してきている.その中でも,全エクソン解析(エクソーム解析)は,約20万個のエクソンをすべて解析するものである.これを発達緑内障早発型の解析に用いた.発達緑内障早発型では,CYP1B1遺伝子が唯一発見されている原因遺伝子であるが,新規原因遺伝子解析のために,今回次世代シークエンサーでの解析に適する症例・家系の収集を行い,エクソーム解析を行った.CYP1B1遺伝子スクリーニングの後,CYP1B1遺伝子変異陰性の症例を用い,エクソーム解析を行った.その結果,発達緑内障早発型では原因遺伝子について遺伝的異質性が高いこと,de novo変異も原因の候補であることを明らかにした.次に,POAGおよびNTGにおける新規原因遺伝子解明のため,POAG1家系,NTG2家系のエクソーム解析を行った.1000 Genomes,SNPデータベースでフィルターをかけ,各々数十個~100個候補遺伝子を抽出した.今回の3家系に共通している候補遺伝子はなく,2家系においては神経系の細胞の分化に関連する転写因子とアクチン関連分子が候補遺伝子であった.また,一般の孤発例にも適用を開始し,この手法は緑内障原因遺伝子の探索に有用と考えられた.ゲノム情報を活用しゲノム医療を現実にするためには,遺伝子,環境,病気の3つの因果関係を明らかにしていかなければならない.今回,東北大学東北メディカル・メガバンクにおいて大規模バイオバンクを構築し,集積される生体試料から疾患と関連する遺伝子の同定と,それらのバイオマーカーの探索を開始した.2013年度中に1,000人(深度30倍以上)の全ゲノム配列解析を実施し,日本人ゲノムのSNPを頻度0.5&#37;以下まで決定して日本人標準ゲノムリファレンスパネルを作成し,疾患感受性と関連する遺伝子を同定する.解析により同定した多型の中から日本人特有のもの,関連遺伝子を抽出し,日本人に最適化した緑内障SNPアレイを開発する.ゲノム情報と健康情報・診療情報とを集約することで,緑内障の予防や診断精度の向上,治療効果の向上のための緑内障個別化医療の実現を目指すことが可能になると期待される.(著者抄録)

  • The Activation of the Wnt3a/beta-Catenin Pathway Induced Maturation of Impaired Neutrophils as Well as the Endoplasmic Reticulum Stress in Induced Pluripotent Stem Cell Derived from a Severe Congenital Neutropenia Patient with ELANE Mutation

    Takafumi Hiramoto, Yasuhiro Ebihara, Yoko Mizoguchi, Kazuhiro Nakamura, Kiyoshi Yamaguchi, Kazuko Ueno, Naoki Nariai, Shinji Mochizuki, Shohei Yamamoto, Masao Nagasaki, Yoichi Furukawa, Kenzaburo Tani, Hiromitsu Nakauchi, Masao Kobayashi, Kohichiro Tsuji

    MOLECULAR THERAPY   2013年6月

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    記述言語:英語  

  • Recurrent Mutations of Multiple Components of Cohesin Complex in Myeloid Neoplasms

    Ayana Kon, Lee-Yung Shih, Masashi Minamino, Masashi Sanada, Yuichi Shiraishi, Yasunobu Nagata, Kenichi Yoshida, Yusuke Okuno, Masashige Bando, Shumpei Ishikawa, Aiko Sato-Otsubo, Genta Nagae, Claudia Haferlach, Daniel Nowak, Yusuke Sato, Tamara Alpermann, Masao Nagasaki, Teppei Shimamura, Hiroko Tanaka, Kenichi Chiba, Ryo Yamamoto, Tomoyuki Yamaguchi, Makoto Otsu, Naoshi Obara, Mamiko Sakata-Yanagimoto, Tsuyoshi Nakamaki, Ken Ishiyama, Florian Nolte, Wolf-Karsten Hofmann, Shuichi Miyawaki, Shigeru Chiba, Hiraku Mori, Hiromitsu Nakauchi, H. Phillip Koeffler, Hiroyuki Aburatani, Torsten Haferlach, Katsuhiko Shirahige, Satoru Miyano, Seishi Ogawa

    BLOOD   2012年11月

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    記述言語:英語  

    DOI: 10.1182/blood.V120.21.782.782

  • Mutations of cohesin genes in myeloid malignancy

    Ayana Kon, Masashi Sanada, Kenichi Yoshida, Yuichi Shiraishi, Yasunobu Nagata, Yusuke Sato, Aiko Sato-Otsubo, Masao Nagasaki, Naoshi Obara, Mamiko Sakata-Yanagimoto, Ken Ishiyama, Hiraku Mori, Shuichi Miyawaki, H. Phillip Koeffler, Lee-Yung Shih, Shigeru Chiba, Satoru Miyano, Seishi Ogawa

    CANCER RESEARCH   2012年4月

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    記述言語:英語  

    DOI: 10.1158/1538-7445.AM2012-5117

  • EGF receptor tyrosine kinase defines critical prognostic genes of stage IA lung adenocarcinoma

    Asuka Nakata, Mai Yamauchi, Rui Yamaguchi, Takashi Kohno, Masao Nagasaki, Teppei Shimamura, Seiya Imoto, Ayumu Saito, Kazuko Ueno, Yousuke Hatanaka, Ryo Yoshida, Tomoyuki Higuchi, Masaharu Nomura, David G. Beer, Jun Yokota, Satoru Miyano, Noriko Gotoh

    CANCER RESEARCH   2012年4月

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    記述言語:英語  

    DOI: 10.1158/1538-7445.AM2012-LB-99

  • Frequent splicing pathway mutations and aberrant RNA splicing in myelodysplasia

    Kenichi Yoshida, Masashi Sanada, Yuichi Shiraishi, Daniel Nowak, Yasunobu Nagata, Ryo Yamamoto, Yusuke Sato, Aiko Sato-Otsubo, Ayana Kon, Masao Nagasaki, George Chalkidis, Yutaka Suzuki, Masashi Shiosaka, Ryoichiro Kawahata, Tomoyuki Yamaguchi, Makoto Otsu, Naoshi Obara, Mamiko Sakata-Yanagimoto, Ken Ishiyama, Hiraku Mori, Florian Nolte, Wolf-Karsten Hofmann, Shuichi Miyawaki, Sumio Sugano, Claudia Haferlach, H. Phillip Koeffler, Lee-Yung Shih, Torsten Haferlach, Shigeru Chiba, Hiromitsu Nakauchi, Satoru Miyano, Seishi Ogawa

    CANCER RESEARCH   2012年4月

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    記述言語:英語  

    DOI: 10.1158/1538-7445.AM2012-5119

  • ダウン症候群に合併した一過性骨髄増殖症(TAM)および急性巨核芽球性白血病(AMKL)の全エクソンシーケンス

    吉田 健一, 土岐 力, 朴 明子, 永田 安伸, 王 汝南, 白石 友一, 真田 昌, 昆 彩菜, 佐藤 亜衣子, 長崎 正朗, 宮野 悟, 金兼 弘和, 川上 清, 加藤 剛二, 小島 勢二, 林 泰秀, 伊藤 悦朗, 小川 誠司

    小児がん   2011年11月

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    記述言語:日本語  

    ダウン症候群に合併した一過性骨髄増殖症(TAM)および急性巨核芽球性白血病(AMKL)の全エクソンシーケンス

  • Frequent Pathway Mutations of Splicing Machinery in Myelodysplasia

    Kenichi Yoshida, Masashi Sanada, Yuichi Shiraishi, Daniel Nowak, Yasunobu Nagata, Ryo Yamamoto, Yusuke Sato, Aiko Sato-Otsubo, Ayana Kon, Masao Nagasaki, George Chalkidis, Yutaka Suzuki, Makoto Otsu, Naoshi Obara, Mamiko Sakata-Yanagimoto, Ken Ishiyama, Hiraku Mori, Florian Nolte, Wolf-Karsten Hofmann, Shuichi Miyawaki, Sumio Sugano, Claudia Haferlach, H. Phillip Koeffler, Lee-Yung Shih, Torsten Haferlach, Shigeru Chiba, Hiromitsu Nakauchi, Satoru Miyano, Seishi Ogawa

    BLOOD   2011年11月

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    記述言語:英語  

  • Functional Analysis of SRSF2 Mutations in Myelodysplastic Syndromes and Related Disorders

    Ayana Kon, Masashi Sanada, Kenichi Yoshida, Yasunobu Nagata, Yuichi Shiraishi, Yusuke Sato, Aiko Sato-Otsubo, Ryo Yamamoto, Masao Nagasaki, Yutaka Suzuki, Tomoyuki Yamaguchi, Makoto Otsu, Sumio Sugano, Shigeru Chiba, H. Phillip Koeffler, Lee-Yung Shih, Hiromitsu Nakauchi, Satoru Miyano, Seishi Ogawa

    BLOOD   2011年11月

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    記述言語:英語  

  • Mutational Spectrum Analysis of Interesting Correlation and Interrelationship Between RNA Splicing Pathway and Commonly Targeted Genes in Myelodysplastic Syndrome

    Yasunobu Nagata, Masashi Sanada, Ayana Kon, Kenichi Yoshida, Yuichi Shiraishi, Aiko Sato-Otsubo, Hiraku Mori, Ken Ishiyama, Mamiko Sakata-Yanagimoto, Naoshi Obara, Masao Nagasaki, Shuichi Miyawaki, Shigeru Chiba, Satoru Miyano, Shih Lee Yung, H. Phillip Koeffler, Seishi Ogawa

    BLOOD   2011年11月

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    記述言語:英語  

    DOI: 10.1182/blood.V118.21.273.273

  • ウイルス性肝細胞がんの全ゲノムシークエンス解析(Whole Genome Sequencing and Analysis of Virus-related Hepatocellular Carcinoma)

    中川 英刀, 藤本 明洋, 角田 達彦, 長崎 正朗, 柴田 龍弘, 十時 泰, 上野 昌樹, 川上 由育, 山田 晃正, 茶山 一彰, 山上 裕機, 宮野 悟, 中村 祐輔

    日本癌学会総会記事   2011年9月

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    記述言語:英語  

    ウイルス性肝細胞がんの全ゲノムシークエンス解析(Whole Genome Sequencing and Analysis of Virus-related Hepatocellular Carcinoma)

  • 心筋細胞におけるグルココルチコイド受容体の役割の解明

    丸山 崇子, 吉川 賢忠, 長崎 正朗, 井元 清哉, 宮野 悟, 徳留 さとり, 佐野 元昭, 福田 恵一, 清水 宣明, 森本 幾夫, 田中 廣壽

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   2010年12月

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    記述言語:日本語  

    心筋細胞におけるグルココルチコイド受容体の役割の解明

  • 生命をシステムとして理解するための計算戦略 : Cell Illustrator の開発

    長崎 正朗, 斉藤 あゆむ, 宮野 悟

    計測と制御 = Journal of the Society of Instrument and Control Engineers   2010年8月

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    記述言語:日本語  

    Computational Strategy for Systems Biology : Development of Cell Illustrator

  • Critical prognostic genes for stage I lung cancer are identified from normal growth factor-regulated gene network by overcoming cancer heterogeneity

    Noriko Gotoh, Mai Yamauchi, Rui Yamauchi, Masao Nagasaki, Teppei Shimamura, Seiya Imoto, Ayumu Saito, Kazuko Ueno, Yousuke Hatanaka, Ryo Yoshida, Tomoyuki Higuchi, Masaharu Nomura, Takashi Kohno, Jun Yokota, David G. Beer, Satoru Miyano

    CANCER RESEARCH   2010年4月

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    記述言語:英語  

    DOI: 10.1158/1538-7445.AM10-LB-132

  • Ligand-based gene expression profiling reveals novel roles of glucocorticoid receptor in the cardiomyocytes

    Noritada Yoshikawa, Motoaki Sano, Satori Tokudome, Noriaki Shimizu, Takako Maruyama, Masao Nagasaki, Seiya Imoto, Satoru Miyano, Yusuke Tagata, Shinobu Nishitani, Kenji Takehana, Keiichi Fukuda, Chikao Morimoto, Hirotoshi Tanaka

    ENDOCRINE JOURNAL   2010年3月

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    記述言語:英語  

  • Identification of new biomarkers and molecular targets of lung cancers by systems biology approach

    Mai Yamauchi, Rui Yamaguchi, Masao Nagasaki, Teppei Shimamura, Seiya Imoto, Ayumu Saito, Kazuko Ueno, Yousuke Hatanaka, Ryo Yoshida, Kazuyuki Okeguchi, Takashi Kohno, Jun Yokota, Satoru Miyano, Noriko Gotoh

    CANCER RESEARCH   2009年5月

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    記述言語:英語  

  • 動的ネットワーク構造探索の計算イニシアティブ バイオマーカー・分子標的探索のための動的ネットワークを予測する計算科学的方法の開発

    井元 清哉, 山口 類, 島村 徹平, 玉田 嘉紀, 長崎 正朗, 斉藤 あゆむ, 植野 和子, 畑中 洋亮, 吉田 亮, 樋口 知之, 山内 麻衣, 後藤 典子, 宮野 悟

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   2008年11月

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    記述言語:日本語  

  • グルココルチコイド 心筋細胞におけるグルココルチコイド受容体標的遺伝子の解明

    吉川 賢忠, 長崎 正朗, 井元 清哉, 宮野 悟, 徳留 さとり, 佐野 元昭, 福田 恵一, 清水 宣明, 森本 幾夫, 田中 廣壽

    日本内分泌学会雑誌   2008年9月

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    記述言語:日本語  

    グルココルチコイド 心筋細胞におけるグルココルチコイド受容体標的遺伝子の解明

  • ペトリネットによる転写制御ネットワークのモデリングと統計的推測

    吉田 亮, 長崎 正郎, 山口 類, 井元 清哉, 宮野 悟, 樋口 知之

    情報処理学会研究報告. BIO, バイオ情報学   2008年6月

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    記述言語:その他  

  • ダイナミックパスウェイモデリング言語:CSML (ゲノムから生命システムへ) -- (ゲノムから情報科学)

    長崎 正朗, 土井 淳, 宮野 悟

    蛋白質核酸酵素   2005年12月

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    記述言語:日本語  

  • Java RMI による Genomic Object Net の分散オブジェクト化(バイオエンジニアリングI)

    河野 智一, 北風 裕教, 長崎 正朗, 土井 淳, 松野 浩嗣, 宮野 悟

    講演論文集   2004年3月

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    記述言語:日本語  

    Study of Constructing a Genomic Object Net System using the Distributed Object : Java RMI

  • An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis

    S Tokuhiro, R Yamada, XT Chang, A Suzuki, Y Kochi, T Sawada, M Suzuki, M Nagasaki, M Ohtsuki, M Ono, H Furukawa, M Nagashima, S Yoshino, A Mabuchi, A Sekine, S Saito, A Takahashi, T Tsunoda, Y Nakamura, K Yamamoto

    NATURE GENETICS   2003年12月

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    記述言語:英語  

    Rheumatoid arthritis is a common inflammatory disease with complex genetic components. We investigated the genetic contribution of the cytokine gene cluster in chromosome 5q31 to susceptibility to rheumatoid arthritis in the Japanese population by case-control linkage disequilibrium (LD) mapping using single nucleotide polymorphisms (SNPs). Here we report that there is significant association between rheumatoid arthritis and the organic cation transporter gene SLC22A4 (P=0.000034). We show that expression of SLC22A4 is specific to hematological and immunological tissues and that SLC22A4 is also highly expressed in the inflammatory joints of mice with collagen-induced arthritis. A SNP affects the transcriptional efficiency of SLC22A4 in vitro, owing to an allelic difference in affinity to Runt-related transcription factor 1 (RUNX1), a transcriptional regulator in the hematopoietic system. A SNP in RUNX1 is also strongly associated with rheumatoid arthritis (P=0.00035). Our data indicate that the regulation of SLC22A4 expression by RUNX1 is associated with susceptibility to rheumatoid arthritis, which may represent an example of an epistatic effect of two genes on this disorder.

    DOI: 10.1038/ng1267

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所属学協会

  • 日本バイオインフォマティクス学会

  • 日本がん学会

  • 日本人類遺伝学会

担当授業科目

  • Medical Life Sciences Ⅰ

    2024年4月 - 2024年6月   春学期

  • 生命医科学Ⅰ

    2024年4月 - 2024年6月   春学期

  • 生命医科学Ⅰ

    2024年4月 - 2024年6月   春学期

  • Medical Life Sciences Ⅰ

    2024年4月 - 2024年6月   春学期

社会貢献・国際連携活動概要

  • 産学連携活動の1つとして「量子計算技術を中心としたゲノム情報解析の応用に関する研究」の共同研究を開始した。

社会貢献活動

  • 研究題目:ネットワーク統計技術とAIの融合によるバイオメディカル大規模解析技術開発とその応用に関する研究 ネットワークAI統計部門の設立と運用を開始した。

    民間機関等:株式会社BlueMeme  2023年10月

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    対象:社会人・一般, 学術団体, 企業, 市民団体, 行政機関

    種別:その他