Functional SNP of ARHGEF10 confers risk of atherothrombotic stroke

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 × 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.

Original languageEnglish
Article numberddp582
Pages (from-to)1137-1146
Number of pages10
JournalHuman molecular genetics
Volume19
Issue number6
DOIs
Publication statusPublished - 01-03-2010

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Matsushita, T., Ashikawa, K., Yonemoto, K., Hirakawa, Y., Hata, J., Amitani, H., Doi, Y., Ninomiya, T., Kitazono, T., Ibayashi, S., Iida, M., Nakamura, Y., Kiyohara, Y., & Kubo, M. (2010). Functional SNP of ARHGEF10 confers risk of atherothrombotic stroke. Human molecular genetics, 19(6), 1137-1146. [ddp582]. https://doi.org/10.1093/hmg/ddp582