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ABSTRACT: Both ulcerative colitis (UC) and Crohn's disease (CD) have a complex etiology involving multiple genetic and environmental factors. Many genome-wide association studies (GWAS) and subsequent replication studies revealed that both diseases share some of the susceptibility loci; however, common genetic factors for both diseases are not fully elucidated. This study is aimed to identify the common genetic factors for CD and UC by a meta-analysis of published studies.
We first reviewed the 10 GWAS for CD to select candidate single nucleotide polymorphisms (SNPs). Next, we performed a PubMed literature search up to June 30, 2010 and carried out a systemic review of published studies that examined the association of CD susceptibility loci in UC patients. Meta-analysis was carried out using the inverse variance-weighted method or the DerSimonian-Laird method after estimating the heterogeneity among the studies. The data for highly linked SNPs were combined. Finally, we performed a meta-analysis of 43 published studies in 45 SNPs located at 33 loci by using a total of 4852 to 31,125 subjects.
We confirmed the association of 17 reported common susceptibility loci. Moreover, we found associations at eight additional loci: GCKR, ATG16L1, CDKAL1, ZNF365, LRRK2-MUC19, C13orf31, PTPN2, and SBNO2. The genetic risk of each locus was modest (odds ratios ranged from 1.05-1.22) except IL23R.
These results indicate that CD and UC share many susceptibility loci with small genetic effect. Our data provide further understanding of the common pathogenesis between CD and UC.
Inflammatory Bowel Diseases 02/2011; 17(12):2407-15. · 4.86 Impact Factor
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Tomonaga Matsushita,
Junji Umeno,
Yoichiro Hirakawa,
Koji Yonemoto,
Kyota Ashikawa,
Hanae Amitani,
Toshiharu Ninomiya,
Jun Hata,
Yasufumi Doi,
Takanari Kitazono,
Mitsuo Iida,
Yusuke Nakamura,
Yutaka Kiyohara,
Michiaki Kubo
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ABSTRACT: Recent genome-wide association study using four prospective population-based cohorts identified two single-nucleotide polymorphisms (SNPs) on chromosome 12p13, rs12425791 and rs11833579, to be significantly associated with the incidence of atherothrombotic stroke. To examine the association of these SNPs with atherothrombotic stroke in the Japanese population, we carried out a case-control association study using a total of 3784 cases and 3102 controls. We also examined the effect of these SNPs on the subtypes of ischemic stroke. Association analysis was carried out using logistic regression model after adjustment of age, sex and cardiovascular risk factors. Rs12425791 was significantly associated with atherothrombotic stroke (P=0.0084, odds ratio (OR)=1.15). When we analyzed effects of rs12425791 on ischemic stroke subtypes, rs12425791 was significantly associated with both small-artery occlusion (P=0.015, OR=1.15) and large-artery atherosclerosis (P=0.024, OR=1.19). Rs11833579 showed no association with atherothrombotic stroke or its subtypes in our population. Our data suggest that rs12425791 on chromosome 12p13 is a genetic marker for atherothrombotic stroke in multiethnic population.
Journal of Human Genetics 05/2010; 55(7):473-6. · 2.57 Impact Factor
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Tomonaga Matsushita,
Kyota Ashikawa,
Koji Yonemoto,
Yoichiro Hirakawa,
Jun Hata,
Hanae Amitani,
Yasufumi Doi,
Toshiharu Ninomiya,
Takanari Kitazono,
Setsuro Ibayashi,
Mitsuo Iida,
Yusuke Nakamura,
Yutaka Kiyohara,
Michiaki Kubo
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ABSTRACT: Although stroke is a common cause of death and a major cause of disability all over the world, genetic components of common forms of ischemic stroke are largely unknown. To identify susceptibility genes of atherothrombotic stroke, we performed a large case-control association study and a replication study in a total of 2775 cases with atherothrombotic stroke and 2839 controls. Through the analysis in 860 cases and 860 age- and sex-matched controls, we found that a single-nucleotide polymorphism (SNP), rs2280887, in the ARHGEF10 gene was significantly associated with atherothrombotic stroke even after the adjustment of multiple testing by a permutation test [unadjusted P = 1.2 x 10(-6), odds ratio = 1.80, 95% confidence interval (CI) = 1.42-2.28]. This association was replicated in independent 1915 cases and 1979 controls. Subsequent fine mapping found another three SNPs which showed similar association due to strong linkage disequilibrium to rs2280887 (r(2) > 0.95). In the functional analyses of these four highly associated SNPs, using luciferase assay and electrophoretic mobility shift assay we found that rs4376531 affected ARHGEF10 transcriptional activity due to the different Sp1-binding affinity. In small GTPase activity assay, we found that a gene product of ARHGEF10 specifically activated RhoA. A population-based cohort study revealed the subjects with rs4376531 CC or CG to increase the incidence of ischemic stroke (P = 0.033, hazard ratio = 1.79, 95% CI = 1.05-3.04). Our data suggest that the functional SNP of ARHGEF10 confers the susceptibility to atherothrombotic stroke.
Human Molecular Genetics 03/2010; 19(6):1137-46. · 7.64 Impact Factor
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Kouichi Asano, Tomonaga Matsushita,
Junji Umeno,
Naoya Hosono,
Atsushi Takahashi,
Takahisa Kawaguchi,
Takayuki Matsumoto,
Toshiyuki Matsui,
Yoichi Kakuta,
Yoshitaka Kinouchi,
Tooru Shimosegawa,
Masayo Hosokawa,
Yoshiaki Arimura,
Yasuhisa Shinomura,
Yutaka Kiyohara,
Tatsuhiko Tsunoda,
Naoyuki Kamatani,
Mitsuo Iida,
Yusuke Nakamura,
Michiaki Kubo
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ABSTRACT: Ulcerative colitis is one of the principal forms of inflammatory bowel disease with complex manifestations. Although previous studies have indicated that there is a genetic contribution to the pathogenesis of ulcerative colitis, the genes influencing susceptibility to the disease have not been fully determined. To identify genetic factors conferring risk of ulcerative colitis, here we conducted a two-stage genome-wide association study and subsequent replication study using 1,384 Japanese individuals with ulcerative colitis and 3,057 control subjects. In addition to the expected strong association with the major histocompatibility complex (MHC) region, we identified three new susceptibility loci: the immunoglobulin receptor gene FCGR2A (rs1801274, P = 1.56 x 10(-12)), a locus on chromosome 13q12 (rs17085007, P = 6.64 x 10(-8)) and the glycoprotein gene SLC26A3 (rs2108225, P = 9.50 x 10(-8)). rs1801274 is a nonsynonymous SNP of FCGR2A that is reported to have a critical effect on receptor binding affinity for IgG and to be associated with other autoimmune diseases. Our findings provide insight into the molecular pathogenesis of ulcerative colitis.
Nature Genetics 11/2009; 41(12):1325-9. · 35.53 Impact Factor
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Tomonaga Matsushita,
Michiaki Kubo,
Koji Yonemoto,
Toshiharu Ninomiya,
Kyota Ashikawa,
Bailing Liang,
Jun Hata,
Yasufumi Doi,
Takanari Kitazono,
Setsuro Ibayashi,
Mitsuo Iida,
Yutaka Kiyohara,
Yusuke Nakamura
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ABSTRACT: After the first genomewide association study of ischemic stroke identified PDE4D as a susceptible gene, many replication studies have been conducted. However, the validity of the association has remained controversial because of the heterogeneity of both genetic markers and phenotypes.
We investigated the association between variations of PDE4D and ischemic stroke by 3 methods: single-marker, haplotype, and tag-single nucleotide polymorphism (SNP) analyses. In the single-marker analysis, we evaluated the association using 2 large case-control samples (1112 cases and 1112 control subjects in a sample obtained from Kyushu, Japan, and 1711 cases and 1786 control subjects in BioBank Japan) and a prospective cohort with 14 years of follow-up. These samples were analyzed both separately and pooled. Haplotype and tag-SNP analyses were performed using the 2 case-control samples together.
In single-marker association tests, we found no significant association in the same direction among the 6 SNP reported in the initial study and ischemic stroke subtypes. Haplotype analysis revealed no significant association between the region around the 5'-end of the gene and combined atherothrombotic and cardioembolic infarction. Rs7730070, a SNP located around the 3'-end of PDE4D, showed the lowest nominal probability value by tag-SNP analysis but was not significant after adjustment for multiple testing (adjusted probability value =0.36).
These results suggest that variations in PDE4D are not associated with ischemic stroke risk in the Japanese population.
Stroke 03/2009; 40(4):1245-51. · 5.73 Impact Factor
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Jun Hata,
Koichi Matsuda,
Toshiharu Ninomiya,
Koji Yonemoto, Tomonaga Matsushita,
Yozo Ohnishi,
Susumu Saito,
Takanari Kitazono,
Setsuro Ibayashi,
Mitsuo Iida,
Yutaka Kiyohara,
Yusuke Nakamura,
Michiaki Kubo
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ABSTRACT: Brain infarction is one of the common causes of death and also a major cause of severe disability. To identify a gene(s) susceptible to brain infarction, we performed a large-scale association study of Japanese patients with brain infarction, using 52608 gene-based single nucleotide polymorphism (SNP) markers. Comparison of allele frequencies between 1112 cases with brain infarction and age- and sex-matched control subjects of the same number found an SNP in the 5'-flanking region of angiotensin receptor like-1 (AGTRL1) gene (rs9943582, - 154G/A) to have a significant association with brain infarction [odds ratio = 1.30, 95% confidence interval (CI) = 1.14-1.47, P = 0.000066]. We also found the binding of Sp1 transcription factor to the region including the susceptible G allele, but not the non-susceptible A allele. Luciferase assay and RT-PCR analysis demonstrated that exogenously introduced Sp1 induced transcription of AGTRL1 and its ligand, apelin, as well, indicating direct regulation of apelin/APJ pathway by Sp1. Furthermore, a 14 year follow-up cohort study in a Japanese community in Hisayama town, Japan revealed that the homozygote of the susceptible G allele of this particular SNP had significantly higher risk of brain infarction (hazard ratio = 2.00, 95% CI = 1.22-3.29, P = 0.006). Our results indicate that the SNP in the AGTRL1 gene is associated with the susceptibility to brain infarction.
Human Molecular Genetics 04/2007; 16(6):630-9. · 7.64 Impact Factor
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Michiaki Kubo,
Jun Hata,
Toshiharu Ninomiya,
Koichi Matsuda,
Koji Yonemoto,
Toshiaki Nakano, Tomonaga Matsushita,
Keiko Yamazaki,
Yozo Ohnishi,
Susumu Saito,
Takanari Kitazono,
Setsuro Ibayashi,
Katsuo Sueishi,
Mitsuo Iida,
Yusuke Nakamura,
Yutaka Kiyohara
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ABSTRACT: Cerebral infarction is the most common type of stroke and often causes long-term disability. To investigate the genetic contribution to cerebral infarction, we conducted a case-control study using 52,608 gene-based tag SNPs selected from the JSNP database. Here we report that a nonsynonymous SNP in a member of protein kinase C (PKC) family, PRKCH, was significantly associated with lacunar infarction in two independent Japanese samples (P = 5.1 x 10(-7), crude odds ratio of 1.40). This SNP is likely to affect PKC activity. Furthermore, a 14-year follow-up cohort study in Hisayama (Fukuoka, Japan) supported involvement of this SNP in the development of cerebral infarction (P = 0.03, age- and sex-adjusted hazard ratio of 2.83). We also found that PKCeta was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and its expression increased as the lesion type progressed. Our results support a role for PRKCH in the pathogenesis of cerebral infarction.
Nature Genetics 03/2007; 39(2):212-7. · 35.53 Impact Factor
