Kyushu University Academic Staff Educational and Research Activities Database
List of Presentations
Takuya Matsushita Last modified date:2019.06.28

Lecturer / Neurology / Kyushu University Hospital


Presentations
1. Takuya Matsushita, Shinya Sato, Ken Yamamoto, Mitsuru Watanabe, Yuri Nakamura, 
Noriko Isobe, Jun-ichi Kira, the Japan Multiple Sclerosis Genetics Consortium , Genome-wide association studies for neuromyelitis optica and the clinical phenotypes., 第60回日本神経学会学術大会, 2019.05.
2. Takuya Matsushita, Shinya Sato, Ken Yamamoto, Mitsuru Watanabe, Yuri Nakamura, Noriko Isobe, Jun-ichi Kira, the Japan Multiple Sclerosis Genetics Consortium , Genetic studies on Japanese multiple sclerosis and neuromyelitis optica spectrum disorders., 第60回日本神経学会学術大会, 2019.05.
3. Matsushita T, Yamamoto K, Nakamura Y, Watanabe M, Shinoda K, Isobe N, Kira J, the Japan MS Genetics Consortium, Difference of tissue-specific networks where the associated genes are densely interconnected between Japanese and European descent patients with MS. , 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis , 2018.10.
4. Takuya Matsushita, Yuri Nakamura, Koji Shinoda, Mitsuru Watanabe, Noriko Isobe, Jun-ichi Kira, the Japan Multiple Sclerosis Genetic Consortium, Difference of genetically aggregated tissue specific networks between Japanese and Caucasian MS, 第59回日本神経学会学術大会, 2018.05.
5. 松下 拓也, 中村 優理, 新野 正明, 深浦 彦彰, 田中 正美, 越智 博文, 神田 隆, 横田 隆徳, 松井 真, 楠 進, 寺山 靖夫, 河内 泉, 大橋 高志, 下濱 俊, 西山 和俊, 中辻 裕司, 錫村 明生, 越智 一秀, 山本 健, CLINICAL AND GENETIC FEATURES OF JAPANESE PATIENTS WITH MULTIPLE SCLEROSIS AND NEUROMYELITIS OPTICA SPECTRUM DISORDER BASED ON JAPAN MULTIPLE SCLEROSIS BIOBANK, The XXIII World Congress of Neurology, 2017.09, Background: We have collected clinical information and biological samples including DNA of Japanese patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) in order to construct a biobank.
Objective: The purpose of this study is to clarify clinical and genetic features of Japanese MS and NMOSD based on the biobank.
Patients and Methods: Demographics and clinical findings collected in the Japan MS biobank were compared between patients with MS and NMOSD. HLA-DRB1 and DPB1 allele were genotyped and the association with the diseases was estimated by logistic regression model.
Results: 344 MS and 125 NMOSD patients were available for this clinical analysis. HLA alleles were genotyped in 387 MS and 143 NMOSD cases. Among the patients with ≥ 10 years of disease duration, ratio of patients with ≤ 2.0 EDSS was 42.8% in MS and 22.0% in NMOSD (p = 0.019). Logistic regression analysis including 394 controls revealed that HLA-DRB1*04:05 and 15:01 were risk alleles and DRB1*09:01, 15:02, 01:01, 13:02, and DPB1*04:01 were protective alleles for MS. DRB1*08:02 and DPB1*05:01 were risk alleles and DRB1*09:01 was protective allele for NMOSD. MS patients with HLA-DRB1*15:01 allele had higher MSSS than patients without the allele (3.84 vs. 3.14, p = 0.018). IgG oligoclonal bands was more frequently positive in MS patients with HLA-DRB1*15:01, and less in patients with DRB1*04:05 than patients without each allele.
Conclusion: These findings suggest that benign clinical course is common in Japanese patients with MS and certain class II HLA alleles are associated with the clinical features in MS.
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6. Takuya Matsushita, Shinya Sato, Ken Yamamoto, Jingcong Zhuang, Yuri Nakamura, Jun-ichi Kira, the Japan Multiple Sclerosis Consortium, Genetic factors associated with clinical phenotypes of multiple sclerosis in the Japanese., 32nd Congress of the European Committee for Treatment and research in Multiple Sclerosis, 2016.09, [Background] Susceptibility to multiple sclerosis (MS) is thought to be influenced by both environmental and genetic factors. With the notable exception of the human leukocyte antigen (HLA) system, genetic factors associated with clinical phenotype have not been yet identified.
[Objective] To clarify genetic factors associated with clinical phenotypes of multiple sclerosis (MS) in Japanese population whose genetic background is relatively homogeneous.
[Method] Genome-wide 600,000 SNPs were genotyped in Japanese MS. Allelic effects for age at onset, MS severity score (MSSS) and positivity of IgG oligoclonal bands (OCB) were calculated based on a linear or logistic regression model. Individual non-MHC MS genetic burden (MSGB) was calculated based on risk variants and the odds ratio of European patients with MS and the associations with clinical phenotypes were tested.
[Results] 553 cases were available for the analyses. rs13202636 (lipoprotein(a)) in chromosome 6 and rs4731427 (leptin) in chromosome 7 were associated with MSSS (p = 3.04e-7 and 2.074e-6 respectively). Lipoprotein(a) (LPA) and leptin were measured in 182 samples from case subjects that had been genotyped in this analysis. The number of the risk allele of rs13202636 was negatively correlated with concentrations of LPA. rs2808707 (Neurotrophic Tyrosine Kinase, Receptor, Type 2 gene, receptor for brain derived neurotrophic factor (BDNF)), was associated with age at onset (p = 2.37e-7). MSGB score was not associated with age at onset or MSSS. Several SNPs in MHC region were also associated with the positivity of OCB and MSGB was higher in patients with OCB than in OCB negative patients (p = 0.0476). The OCB positivity was negatively and positively correlated with HLA-DRB1*04:05 and DRB1*15:01 respectively in multivariate analysis.
[Conclusion] Several genetic loci relating to lipid metabolisms were associated with disability progression of Japanese patients with MS. BDNF may influence age at onset of MS. CSF IgG abnormality was associated with MHC variants in Japanese patients with MS as in people with MS of European descent. HLA-DRB1 alleles were associated with the positivity of OCB and aggregation of risk variants for MS in people of European descent weakly influences OCB positivity..
7. 松下 拓也, 佐藤 眞也, 山本 健, 荘 景聡, 劉 志文, 中村 優理, Clinical and genetic factors associated with disability in Japanese patients with multiple sclerosis, 第57回日本神経学会学術大会, 2016.05, Objective: To clarify clinical and genetic factors associated with disability in Japanese patients with multiple sclerosis (MS).
Methods: Clinical information and DNA samples of patients with MS were collected from seven institutes in Japan. Clinical factors associated with MS severity score (MSSS) were examined. Genome-wide SNPs and four- digit HLA-DRB1 alleles were genotyped for the collected samples and allelic effects for MSSS were estimated. Upper cervical spinal cord areas in MRI were measured among patients and genetic factors associated with spinal cord atrophy were examined.
Results: 528 Japanese cases were available and spinal cord areas were measured in 203 cases. Age at onset positively correlated with MSSS (rho=0.21, p=6.2e-7) and male tended to have a higher MSSS than female. HLA-DRB1*04:05 was negatively associated with MSSS (pcorr=0.048). rs13202636 (lipoprotein(a): LPA) and rs4731427 (leptin) were associated with MSSS (p = 3.04e-7 and 2.074e-6 respectively). Concentrations of LPA and leptin were measured in 182 sera from case subjects that had been genotyped in this study. Individuals homozygous of rs13202636 risk allele had a lower concentration of LPA than individuals without the risk allele (p = 0.011). Cervical spinal cord areas were not associated with any HLA-DRB1 alleles and four SNPs were suggestively associated with spinal cord atrophy (p < 1.0e-5) .
Conclusion: HLA-DRB1*04:05 and some variants outside of the MHC were associated with MSSS. Suggestive loci associated with spinal cord atrophy were found..
8. Takuya Matsushita, Potential Biomarkers for MS in Asians, 8th Congress of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis, 2015.11, Multiple sclerosis (MS) has a heterogeneous phenotype and disease course. It is very important to identify a good biomarker, which can distinguish between MS and other neuroinflammatory diseases and detect inflammatory activity and the degree of neurodegeneration as well as effectiveness of the treatments. However, validated and clinically useful biomarkers have not been identified. Thus, current diagnostic criteria are based on the combination of clinical manifestations, magnetic resonance imaging (MRI) findings, and CSF IgG abnormalities, that are not specific for MS. Diagnosis of MS in Asians are relatively difficult because the abnormalities in Asians are less common than in people of European descent. The disease course is also different from MS of European descent. The appropriate biomarkers for Asians have been desired for a long time. Recent studies have revealed several biomarkers for diagnosis, disease activity and response to the therapy in Asian. Findings of genome-wide association study in the Japanese suggest that lipid metabolism affects the clinical course. A lipoprotein and leptin are possible biomarkers for the disability progression. We will discuss potential biomarkers in MS of Asian referring to recent studies. The application of reliable biomarkers could totally alter the management of MS and help refine treatment strategies for preventing progression of neurological disability..
9. Takuya Matsushita, Shinya Sato, Ken Yamamoto, Yuri Nakamura, Jun-ichi Kira, the Japane Multiple Sclerosis Genetics Consortium, Genome-wide association study (GWAS) for clinical phenotypes of multiple sclerosis in the Japanese., 8th Congress of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis, 2015.11, [Objective] To clarify genetic factors associated with clinical phenotypes of multiple sclerosis (MS) in Japanese population.
[Method] Genome-wide 600,000 SNPs were genotyped in Japanese MS. Allelic effects for age of onset, MS severity score (MSSS) and positivity of IgG oligoclonal bands (OCB) were calculated based on a linear or logistic regression model including age of onset or gender as covariates. Quartiles of MSSS were used for the phenotypic values.
[Results] 553 cases were available for the analyses. rs13202636 (lipoprotein(a)) in chromosome 6 and rs4731427 (leptin) in chromosome 7 were associated with MSSS (p = 3.04e-7 and 2.074e-6 respectively). Lipoprotein(a) (LPA) was measured by means of latex agglutination turbidimetry and leptin was measured by ELISA in 182 sera from case subjects that had been genotyped in this analysis. The number of the risk allele of rs13202636 was negatively correlated with concentrations of LPA. Individuals homozygous for the risk allele had a lower concentration of LPA than individuals without the risk allele (p = 0.011). There was no correlation between the number of rs4731427 allele and concentrations of leptin. rs2808707 (Neurotrophic Tyrosine Kinase, Receptor, Type 2 gene) was associated with age of onset (p = 2.37e-7). Several SNPs in MHC region were also associated with the positivity of OCB.
[Conclusion] Genetic loci relating to lipid metabolisms were associated with disability progression of Japanese MS. CSF IgG abnormality was associated with MHC in the Japanese like MS of European descent..
10. 松下 拓也, 佐藤 眞也, 山本 健, Jun-ichi Kira, Genetic factors associated with clinical phenotypes of multiple sclerosis, 第56回日本神経学会学術大会, 2015.05, [Objective] To clarify genetic factors which are associated with clinical phenotypes of multiple sclerosis (MS) in the Japanese population.
[Method] Genome-wide 600,000 SNPs were genotyped in MS of the Japanese population. The association of SNP with clinical phenotypes of MS was tested by using linear regression analysis or Cochran-Armitage trend test. The age of onset, MS Severity Score (MSSS) calculated from the disease duration and the Expanded Disability Status Scale (EDSS) score, the positivity of oligoclonal bands (OCB), and the fulfillment of Barkhof’s criteria were included in the clinical phenotypes. The MS genetic burden (MSGB) score was calculated in each individual based on the established risk SNPs outside major histocompatibility complex (MHC) region for European descent MS and the correlation with the phenotypes were analyzed.
[Results] 553 cases were available for the analyses. rs7679359 in chromosome 4 was significantly associated with the age of onset (p = 4.7 × 10-9). Several SNPs in MHC region were also associated with the positivity of OCB. SNP rs16987159 was associated with MSSS, though the p value was not genome-wide significant (p = 8.6 × 10-7). MSGB score was weakly correlated with MSSS (ρ = 0.086, p = 0.049) and higher in patients with OCB or brain lesions fulfilling Barkhof’s criteria than in patients without such phenotypes (p = 0.048 and 0.00049).
[Conclusion] Some SNPs were associated with clinical phenotypes of MS. MSGB calculated from risk SNPs for European MS was correlated with OCB positivity and multiple brain lesions..
11. Takuya Matsushita, Shinya Sato, Ken Yamamoto, Lohith Madireddy, Pierre Gourraud, Sergio Baranzini, Jorge Oksenberg, Jun-ichi Kira, Japan MS Genetic Consortium, Genome-wide Association Study for Multiple Sclerosis and Neuromyelitis Optica in the Japanese Population, 7th Congress of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis, 2014.11, Background: Multiple sclerosis (MS) and neuromyelitis optica (NMO) are complex diseases that involve both environmental and genetic factors. While genetic risk variants for MS have been identified among European by genome-wide association studies (GWAS), the variants have not been clarified in Asians.
Objective: To clarify genetic risk variants for MS and NMO in the Japanese population.
Methods: A GWAS was conducted using 533 cases with MS and 1,798 controls, and 200 cases with NMO and 1,752 controls. MS genetic burden (MSGB) score was calculated based on non-MHC established risk variants for European MS. HLA-DRB1 and DPB1 alleles were determined in 508 cases with MS, 193 with NMO and 334 controls.
Results: Twenty-six loci (FDR corrected p < 0.05) associated with MS and 33 suggestive loci (p < 1.0×10-4) associated with NMO were identified outside the MHC. There was no common risk region between MS and NMO. Thirteen SNPs out of the 97 risk variants for European MS were replicated (p < 0.05) in the Japanese population. MSGB score was significantly higher in cases with MS than in controls (p < 2.2e-16). HLA-DRB1*04:05 and 15:01 were risk and DRB1*13:02, 01:01, and 09:01 were protective alleles for MS. HLA-DRB1*08:02 and 16:02, and DPB1*05:01 were risk alleles and DRB1*09:01 was protective allele for NMO.
Conclusion: GWAS in the Japanese population identified novel genetic risks for MS and NMO. MSGB indicated common genetic effects for MS between European and Japanese. Genetic loci associated with MS seemed to be different from loci associated with NMO..
12. Takuya Matsushita, Shinya Sato, Ken Yamamoto, Lohith Madireddy, Pierre-Antoine Gaurraud, Sergio Baranzini, Jorge Oksenberg, Jun-ichi Kira, Susceptibility variants for multiple sclerosis in the Japanese population, Joint ACTRIMS-ECTRIMS meeting, 2014.10, Background: Multiple sclerosis (MS) is characterized by temporal and spatial dissemination of demyelination in central nervous system. Susceptibility to MS is thought to be influenced by both environmental and genetic factors. Ethnicity is one of such risk factors. MS is most prevalent among people of Northern European descent, and uncommon in people of Asian. While genetic risk variants for MS have been identified among people of European descent by genome-wide association study (GWAS), the variants are not elucidated among Asians.
Objectives: To clarify susceptibility variants for Japanese MS by GWAS and replication or difference of the risks between people of European descent and Japanese.
Methods: Genome-wide SNPs were genotyped in 275 MS cases and 974 controls for a discovery dataset and in 297 cases and 944 controls for a replication dataset in the Japanese population and the allelic effects for MS were calculated. Individual MS genetic burden (MSGB) was calculated based on reported 110 risk variants in people of European descent. Four-digit type of HLA-DRB1 was determined in 508 cases and 334 controls among these individuals.
Results: GWAS for 553 cases and 1,798 controls of Japanese identified 26 risk loci (FDR corrected p < 0.05). Two loci (CD58 and ZNF438) were reported in European study and the others were novel in the Japanese population. In SNP level, 13 SNPs out of reported 97 risk variants were replicated (p < 0.05). MSGB score based on 99 risk SNPs was significantly higher in cases than in controls (p < 2.2e-16, Nagelkerke’s R2 = 0.0485). HLA-DRB1*04:05 and 15:01 were risk alleles and DRB1*13:02, 01:01, and 09:01 were protective alleles for MS.
Conclusions: GWAS in the Japanese population identified novel genetic risks for MS. MSGB showed common genetic effect for MS between people of Japanese and European descent..