Functional SNP of ARHGEF10 confers risk of atherothrombotic stroke

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...

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Bibliographic Details
Published in:Human molecular genetics 2010-03, Vol.19 (6), p.1137-1146
Main Authors: Matsushita, Tomonaga, Ashikawa, Kyota, Yonemoto, Koji, Hirakawa, Yoichiro, Hata, Jun, Amitani, Hanae, Doi, Yasufumi, Ninomiya, Toshiharu, Kitazono, Takanari, Ibayashi, Setsuro, Iida, Mitsuo, Nakamura, Yusuke, Kiyohara, Yutaka, Kubo, Michiaki
Format: Article
Language:English
Subjects:
Alleles
Biological and medical sciences
Brain Ischemia - complications
Brain Ischemia - epidemiology
Brain Ischemia - genetics
Case-Control Studies
Cell Line, Tumor
Enzyme Activation
Exons - genetics
Fundamental and applied biological sciences. Psychology
Genetic Predisposition to Disease
Genetics of eukaryotes. Biological and molecular evolution
Genome-Wide Association Study
Guanine Nucleotide Exchange Factors - genetics
Humans
Incidence
Introns - genetics
Japan - epidemiology
Kaplan-Meier Estimate
Linkage Disequilibrium - genetics
Medical sciences
Molecular and cellular biology
Neurology
Polymorphism, Single Nucleotide - genetics
Protein Binding
Rho Guanine Nucleotide Exchange Factors
rhoA GTP-Binding Protein - metabolism
Sp1 Transcription Factor - metabolism
Stroke - complications
Stroke - epidemiology
Stroke - genetics
Thrombosis - complications
Thrombosis - genetics
Transcription, Genetic
Vascular diseases and vascular malformations of the nervous system
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Summary: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 × 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 (r2 > 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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddp582