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 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.
Matsushita
Tomonaga
T
Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, Yokohama, Kanagawa, Japan.
Ashikawa
Kyota
K
Yonemoto
Koji
K
Hirakawa
Yoichiro
Y
Hata
Jun
J
Amitani
Hanae
H
Doi
Yasufumi
Y
Ninomiya
Toshiharu
T
Kitazono
Takanari
T
Ibayashi
Setsuro
S
Iida
Mitsuo
M
Nakamura
Yusuke
Y
Kiyohara
Yutaka
Y
Kubo
Michiaki
M
D000483:Alleles; D002545:Brain Ischemia / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D015994:Incidence; D007438:Introns / Q000235:genetics; D007564:Japan / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D015810:Linkage Disequilibrium / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011485:Protein Binding; D064067:Rho Guanine Nucleotide Exchange Factors; D016329:Sp1 Transcription Factor / Q000378:metabolism; D020521:Stroke / Q000150:complications* / Q000453:epidemiology / Q000235:genetics*; D013927:Thrombosis / Q000150:complications* / Q000235:genetics*; D014158:Transcription, Genetic; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
C577232:ARHGEF10 protein, human; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; D016329:Sp1 Transcription Factor; D020742:rhoA GTP-Binding Protein