|Atsushi Hirano||Last modified date：2019.06.27|
Assistant Professor / Department of Medicine and Clinical Science / Department of Clinical Medicine / Faculty of Medical Sciences
|Atsushi Hirano||Last modified date：2019.06.27|
|1.||Keiko Yamazaki, Junji Umeno, Atsushi Takahashi, Atsushi Hirano, Todd Andrew Johnson, Natsuhiko Kumasaka, Takashi Morizono, Naoya Hosono, Takaaki Kawaguchi, Masakazu Takazoe, Tetsuhiro Yamada, Yasuo Suzuki, Hiroki Tanaka, Satoshi Motoya, Masayo Hosokawa, Yoshiaki Arimura, Yasuhisa Shinomura, Toshiyuki Matsui, Takayuki Matsumoto, Mitsuo Iida, Tatsuhiko Tsunoda, Yusuke Nakamura, Naoyuki Kamatani, Michiaki Kubo, A genome-wide association study identifies 2 susceptibility loci for crohn's disease in a Japanese population, Gastroenterology, 10.1053/j.gastro.2012.12.021, 144, 4, 781-788, 2013.04, Background & Aims: Crohn's disease is an inflammatory bowel disease induced by multiple genetic and environmental factors. Genome-wide association studies have identified genetic factors that affect the risk for Crohn's disease in European populations, but information from other ethnic groups is scarce. We therefore investigated genetic factors associated with Crohn's disease in the Japanese population. Methods: We performed a genome-wide association study with 372 individuals with Crohn's disease (cases) and 3389 controls, all from the Japanese population. To confirm identified associations, we performed a replication study with an independent panel of 1151 Crohn's disease cases and 15,800 controls. We also performed an association analysis using genome-wide genotype imputation in the discovery cohort. Results: We confirmed associations of Crohn's disease with variants in MHC (rs7765379, P = 2.11 × 10 -59), TNFSF15 (rs6478106, P = 3.87 × 10-45), and STAT3 (rs9891119, P = 2.24 × 10-14). We identified 2 new susceptibility loci: on chromosome 4p14 (rs1487630, P = 2.40 × 10 -11; odds ratio, 1.33), and in the SLC25A15-ELF1-WBP4 region on 13q14 (rs7329174 in ELF1, P = 5.12 × 10-9; odds ratio, 1.27). Conclusions: In a genome-wide association study, we identified 2 new susceptibility loci for Crohn's disease in a Japanese population. These findings could increase our understanding of the pathogenesis of Crohn's disease..|
|2.||Kouichi Asano, Takayuki Matsumoto, Junji Umeno, Atsushi Hirano, Motohiro Esaki, Naoya Hosono, Toshiyuki Matsui, Yutaka Kiyohara, Yusuke Nakamura, Michiaki Kubo, Takanari Kitazono, Impact of allele copy number of polymorphisms in FCGR3A and FCGR3B genes on susceptibility to ulcerative colitis, Inflammatory Bowel Diseases, 10.1097/MIB.0b013e318298118e, 19, 10, 2061-2068, 2013.09, Background: Polymorphisms in the Fcγ receptor genes have been implicated in several autoimmune diseases, including ulcerative colitis (UC). However, most of these reports had not taken into account the effect of copy number variation at this region. Methods: We investigated the combined effect of allele and gene copy number of FCGR3A-158F/V and FCGR3B-NA1/NA2 on susceptibility to UC. Study subjects were composed of a total of 752 Japanese patients with UC and 2062 Japanese control subjects. To estimate allele copy number of the 2 polymorphisms, we integrated the results of PCR-based real-time Invader assay (PCR-RETINA) that measures the allelic ratio and Taqman assay that detects the total copy number. We analyzed the associations of allele copy number with UC using logistic regression model. Results: Gene and allele copy numbers of FCGR3A and FCGR3B were successfully determined in more than 99.5% of the study subjects. Allele copy number of FCGR3A-158F/V demonstrated significant association with susceptibility to UC (P = 0.02), although each single-nucleotide polymorphism and copy number variation alone did not show significant association. Although allele copy number of FCGR3B-NA1/NA2 (P = 0.002) also showed significant association with UC susceptibility, this association seemed to reflect the effect of FCGR3B gene copy number. Subsequent haplotype analyses revealed a strong association of a haplotype FCGR2A-131H/R and copy number of FCGR3B gene (P = 6.5 × 10-9). Conclusions: Allele copy number of FCGR3A-158F/V and FCGR3B gene copy number were associated with UC susceptibility. Our results suggest that organizing handling of immune complex by FCGR3A, FCGR3B, and FCGR2A may play a crucial role in the pathogenesis of UC..|
|3.||Yuji Maehata, Atsushi Hirano, Shunichi Yanai, Hiroshi Kawano, Case presentations
Flat/small protrusions, Endoscopy in the Diagnosis of Small Intestine Diseases, 10.1007/978-4-431-54352-7_14, 69-75, 2014.01, Per-oral DBE showed a semi-pedunculated protrusion in the jejunum. The surface was nodular and whitish..
|4.||Kouichi Asano, Motohiro Esaki, Junji Umeno, Atsushi Hirano, Yuji Maehata, Moriyama Tomohiko, Shotaro Nakamura, Takayuki Matsumoto, Takanari Kitazono, Contribution of susceptibility variants at FCGR2A and 13q12 to the risk of relapse among Japanese patients with ulcerative colitis, Journal of Gastroenterology, 10.1007/s00535-015-1062-3, 50, 11, 1094-1102, 2015.03, Background: Recent genome-wide association studies have identified nearly 100 susceptibility genes for ulcerative colitis (UC). However, the contribution of susceptibility variants for UC to clinical outcome has scarcely been reported. The aim of this study was to investigate whether UC-associated genetic variants confer a risk of clinical relapse. Methods: One hundred and nine consecutive Japanese subjects with quiescent UC were recruited. Four genetic variants of HLA-DRB1*1502, rs6671847 at FCGR2A, rs17085007 at 13q12, and rs2108225 at SLC26A3 were genotyped by Invader assay. The clinical courses were followed after blood sampling, and the risk of relapse according to these genotypes was calculated by Cox proportional hazard model. Results: During the mean follow-up period of 35 months (range 1–81 months), 49 of 109 subjects (45 %) relapsed. Carriers of the G allele of rs6671847 showed an increased risk of relapse compared with non-carriers [adjusted hazard ratio (HR), 2.27; 95 % confidence interval (CI), 1.20–4.32; p = 0.01]. Patients with the CT or TT genotypes of rs17085007 also had an increased risk of relapse compared to subjects with the CC genotype (for CT: adjusted HR, 2.16; 95 % CI, 1.10–4.23; p = 0.03; for TT: adjusted HR, 3.25; 95 % CI, 1.18–8.95; p = 0.02). These two risk variants multiplied the risk of relapse by 2.74 times (95 % CI, 1.10–4.23; p = 0.01) in patients with one risk genotype and 5.40 times (95 % CI, 2.06–14.13; p = 0.0006) in patients with both risk genotypes. Conclusions: Genetic variants of rs6671847 at FCGR2A and rs17085007 at 13q12 conferred a risk of relapse in patients with UC..|
|5.||Atsushi Hirano, Tomoyuki Ohara, Atsushi Takahashi, Masayuki Aoki, Yuta Fuyuno, Kyota Ashikawa, Takashi Morihara, Masatoshi Takeda, Kouzin Kamino, Etsuko Oshima, Yuko Okahisa, Nobuto Shibata, Heii Arai, Hiroyasu Akatsu, Masashi Ikeda, Nakao Iwata, Toshiharu Ninomiya, Akira Monji, Takanari Kitazono, Yutaka Kiyohara, Michiaki Kubo, Shigenobu Kanba, A genome-wide association study of late-onset Alzheimer's disease in a Japanese population, Psychiatric Genetics, 10.1097/YPG.0000000000000090, 25, 4, 139-146, 2015.08, Objective: Although a number of genome-wide association studies (GWASs) of late-onset Alzheimer's disease (LOAD) have been carried out, there have been little GWAS data on East Asian populations. Design: To discover the novel susceptibility loci of LOAD, we carried out a GWAS using 816 LOAD cases and 7992 controls with a replication analysis using an independent panel of 1011 LOAD cases and 7212 controls in a Japanese population. In addition, we carried out a stratified analysis by APOE-ε4 status to eliminate the established effect of APOE region. Results: Our data indicated that 18p11.32 (rs1992269, P =9.77× 10-7), CNTNAP2 (rs802571, P= 1.26×10-6), and 12q24.23 (rs11613092, P =6.85×10-6) were suggestive loci for susceptibility to LOAD. Conclusion: We identified three suggestive loci for susceptibility to LOAD in a Japanese population. Among these, rs802571, located at intron 1 of CNTNAP2, was considered to be a plausible candidate locus from a functional perspective..|
|6.||Yasuhiro Idewaki, Masanori Iwase, Hiroki Fujii, Toshiaki Ohkuma, Hitoshi Ide, Shinako Kaizu, Tamaki Jodai, Yohei Kikuchi, Atsushi Hirano, Udai Nakamura, Michiaki Kubo, Takanari Kitazono, Association of genetically determined aldehyde dehydrogenase 2 activity with diabetic complications in relation to alcohol consumption in Japanese patients with type 2 diabetes mellitus
The fukuoka diabetes registry, PLoS One, 10.1371/journal.pone.0143288, 10, 11, 2015.11, Aldehyde dehydrogenase 2 (ALDH2) detoxifies aldehyde produced during ethanol metabolism and oxidative stress. A genetic defect in this enzyme is common in East Asians and determines alcohol consumption behaviors. We investigated the impact of genetically determined ALDH2 activity on diabetic microvascular and macrovascular complications in relation to drinking habits in Japanese patients with type 2 diabetes mellitus. An ALDH2 singlenucleotide polymorphism (rs671) was genotyped in 4,400 patients. Additionally, the relationship of clinical characteristics with ALDH2 activity (ALDH2 ∗1/∗1 active enzyme activity vs. ∗1/∗2 or ∗2/∗2 inactive enzyme activity) and drinking habits (lifetime abstainers vs. former or current drinkers) was investigated cross-sectionally (n = 691 in ∗1/∗1 abstainers, n = 1,315 in abstainers with ∗2, n = 1,711 in ∗1/∗1 drinkers, n = 683 in drinkers with ∗2). The multiple logistic regression analysis for diabetic complications was adjusted for age, sex, current smoking habits, leisure-time physical activity, depressive symptoms, diabetes duration, body mass index, hemoglobin A1c, insulin use, high-density lipoprotein cholesterol, systolic blood pressure and renin-angiotensin system inhibitors use. Albuminuria prevalence was significantly lower in the drinkers with ∗2 than that of other groups (odds ratio [95% confidence interval (CI)]: ∗1/∗1 abstainers as the referent, 0.94 [0.76-1.16] in abstainers with ∗2, 1.00 [0.80-1.26] in ∗1/∗1 drinkers, 0.71 [0.54-0.93] in drinkers with ∗2). Retinal photocoagulation prevalence was also lower in drinkers with ALDH2 ∗2 than that of other groups. In contrast, myocardial infarction was significantly increased in ALDH2 ∗2 carriers compared with that in ALDH2 ∗1/∗1 abstainers (odds ratio [95% CI]: ∗1/∗1 abstainers as the referent, 2.63 [1.28-6.13] in abstainers with ∗2, 1.89 [0.89-4.51] in ∗1/∗1 drinkers, 2.35 [1.06-5.79] in drinkers with ∗2). In summary, patients with type 2 diabetes and ALDH2 ∗2 displayed a lower microvascular complication prevalence associated with alcohol consumption but a higher macrovascular complication prevalence irrespective of alcohol consumption..
|7.||Junji Umeno, Tadakazu Hisamatsu, Motohiro Esaki, Atsushi Hirano, Naoya Kubokura, Kouichi Asano, Shuji Kochi, Shunichi Yanai, Yuta Fuyuno, Katsuyoshi Shimamura, Naoki Hosoe, Haruhiko Ogata, Takashi Watanabe, Kunihiko Aoyagi, Hidehisa Ooi, Kenji Watanabe, Shigeyoshi Yasukawa, Fumihito Hirai, Toshiyuki Matsui, Mitsuo Iida, Tsuneyoshi Yao, Toshifumi Hibi, Kenjiro Kosaki, Takanori Kanai, Takanari Kitazono, Takayuki Matsumoto, A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter, PLoS Genetics, 10.1371/journal.pgen.1005581, 11, 11, 2015.11, Previously, we proposed a rare autosomal recessive inherited enteropathy characterized by persistent blood and protein loss from the small intestine as chronic nonspecific multiple ulcers of the small intestine (CNSU). By whole-exome sequencing in five Japanese patients with CNSU and one unaffected individual, we found four candidate mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. The pathogenicity of the mutations was supported by segregation analysis and genotyping data in controls. By Sanger sequencing of the coding regions, 11 of 12 other CNSU patients and 2 of 603 patients with a diagnosis of Crohn’s disease were found to have homozygous or compound heterozygous SLCO2A1 mutations. In total, we identified recessive SLCO2A1 mutations located at seven sites. Using RT-PCR, we demonstrated that the identified splice-site mutations altered the RNA splicing, and introduced a premature stop codon. Tracer prostaglandin E2 uptake analysis showed that the mutant SLCO2A1 protein for each mutation exhibited impaired prostaglandin transport. Immunohistochemistry and immunofluorescence analyses revealed that SLCO2A1 protein was expressed on the cellular membrane of vascular endothelial cells in the small intestinal mucosa in control subjects, but was not detected in affected individuals. These findings indicate that loss-of-function mutations in the SLCO2A1 gene encoding a prostaglandin transporter cause the hereditary enteropathy CNSU. We suggest a more appropriate nomenclature of “chronic enteropathy associated with SLCO2A1 gene” (CEAS)..|
|8.||Y. Nuki, J. Umeno, E. Washio, Y. Maehata, Atsushi Hirano, M. Miyazaki, H. Kobayashi, Takanari Kitazono, T. Matsumoto, Motohiro Esaki, The influence of CYP2C19 polymorphisms on exacerbating effect of rabeprazole in celecoxib-induced small bowel injury, Alimentary Pharmacology and Therapeutics, 10.1111/apt.14134, 46, 3, 331-336, 2017.08, Background: Simultaneous use of proton pump inhibitors (PPIs) has been shown to increase the risk of nonsteroidal anti-inflammatory drug (NSAID)-induced small bowel injury. Aim: To investigate whether polymorphisms of the cytochrome P450 2C19 gene (CYP2C19), encoding a key metabolising enzyme for PPIs, are associated with small bowel injury induced by celecoxib in combination with the PPI rabeprazole. Methods: Study participants included 55 healthy Japanese volunteers, who participated in the PPI-NSAID Kyushu University Study using video capsule endoscopy. For 2 weeks, 26 subjects were treated with celecoxib plus rabeprazole (rabeprazole group), and 29 subjects received celecoxib plus placebo (placebo group). All subjects were genotyped for CYP2C19 using real-time fluorescent polymerase chain reaction. Subjects were sub-classified as poor metabolizers or extensive metabolizers. The incidence and number of small bowel injuries were compared between poor metabolizers and extensive metabolizers in each group. Results: In the rabeprazole group, the incidence of small bowel injuries was significantly higher in poor metabolizers than in extensive metabolizers (85.7% vs 31.6%, P=.026). The number of mucosal injuries in the rabeprazole group was also significantly higher in poor metabolizers compared with extensive metabolizers (median [range] 3 [0-31] vs 0 [0-7], P=.01). In addition, we found a significant interaction between CYP2C19 genotype and concomitant use of rabeprazole in subjects at risk for celecoxib-induced small bowel injury. Conclusions: The CYP2C19 genotype might be associated with the risk of small bowel injury when celecoxib is combined with rabeprazole..|
|9.||Akiko Sumi, Udai Nakamura, Masanori Iwase, Hiroki Fujii, Toshiaki Ohkuma, Hitoshi Ide, Tamaki Jodai-Kitamura, Yuji Komorita, Masahito Yoshinari, Yoichiro Hirakawa, Atsushi Hirano, Michiaki Kubo, Takanari Kitazono, The gene-treatment interaction of paraoxonase-1 gene polymorphism and statin therapy on insulin secretion in Japanese patients with type 2 diabetes
Fukuoka diabetes registry, BMC Medical Genetics, 10.1186/s12881-017-0509-1, 18, 1, 2017.12, Background: Although statins deteriorate glucose metabolism, their glucose-lowering effects have emerged in some situations. Here, we assessed whether these effects are a consequence of statins' interaction with paraoxonase (PON)1 enzyme polymorphism. Methods: Adult Japanese type 2 diabetes patients (n=3798) were enrolled in a cross-sectional study. We used Q192R polymorphism of the PON1 gene as a representative single-nucleotide polymorphism and focused on the effects of the wild-type Q allele, in an additive manner. For patients with and without statin therapy, the associations of this allele with fasting plasma glucose (FPG), HbA1c, C-peptide, HOMA2-%β, and HOMA2-IR were investigated separately using a linear regression model, and were compared between groups by testing interactions. Sensitivity analyses were performed using propensity score to further control the imbalance of characteristics between groups. Results: Among patients with statin therapy, there were linear associations of the number of Q alleles with decreased FPG and HbA1c, and with increased serum C peptide and HOMA2-%β (all P<0.01 for trends), while such associations were not observed among those without statin therapy. These differences were statistically significant only for serum C peptide and HOMA2-%β (P<0.01 for interactions). These associations remained significant after multiple explanatory variable adjustment. Sensitivity analyses using propensity score showed broad consistency of these associations. Conclusions: Patients with the Q allele of the PON1 Q192R polymorphism who were treated with statins exhibited improvement in glucose metabolism, especially in insulin secretion, suggesting the importance of genotyping PON1 Q192R to identify those who could benefit from statin therapy..
|10.||Atsushi Hirano, Junji Umeno, Yasuharu Okamoto, Hiroki Shibata, Yoshitoshi Ogura, Moriyama Tomohiko, takehiro torisu, Shin Fujioka, Yuta Fuyuno, Yutaka Kawarabayasi, Takayuki Matsumoto, Takanari Kitazono, Motohiro Esaki, Comparison of the microbial community structure between inflamed and non-inflamed sites in patients with ulcerative colitis, Journal of Gastroenterology and Hepatology (Australia), 10.1111/jgh.14129, 2018.01, Background and Aim: The gut microbiota is suggested to play an important role in the pathogenesis of ulcerative colitis (UC). However, interindividual and spatial variations hamper the identification of UC-related changes. We thus investigated paired mucosa-associated microbiota obtained from both inflamed and non-inflamed sites of UC patients and corresponding sites of non-inflammatory bowel disease (IBD) controls. Methods: Mucosal biopsies of both inflamed and non-inflamed sites were obtained from 14 patients with active UC of the left-sided or proctitis type. Paired mucosal biopsies of the corresponding sites were obtained from 14 non-IBD controls. The microbial community structure was investigated using 16S ribosomal RNA gene sequences, followed by data analysis using qiime and LEfSe softwares. Results: Microbial alpha diversity in both inflamed and non-inflamed sites was significantly lower in UC patients compared with non-IBD controls. There were more microbes of the genus Cloacibacterium and the Tissierellaceae family, and there were less microbes of the genus Neisseria at the inflamed site when compared with the non-inflamed site in UC patients. Decreased abundance of the genera Prevotella, Eubacterium, Neisseria, Leptotrichia, Bilophila, Desulfovibrio, and Butyricimonas was evident at the inflamed site of UC patients compared with the corresponding site of non-IBD controls. Among these taxa, the genera Prevotella and Butyricimonas were also less abundant at the non-inflamed site of UC patients compared with the corresponding site in non-IBD controls. Conclusions: Mucosal microbial dysbiosis occurs at both inflamed and non-inflamed sites in UC patients. The taxa showing altered abundance in UC patients might mediate colonic inflammation..|