Functional SNP of ARHGEF10 confers risk of atherothrombotic stroke
Functional SNP of ARHGEF10 confers risk of atherothrombotic stroke
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DOI：
10.1093/hmg/ddp582
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发表时间：
2010-03-15
影响因子：
3.5
通讯作者：
Kubo, Michiaki
中科院分区：
文献类型：
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作者：
Matsushita, Tomonaga;Ashikawa, Kyota;Kubo, Michiaki
尽管中风是全世界常见的死亡原因和致残的主要原因，但常见形式的缺血性中风的遗传成分在很大程度上尚不清楚。为了确定动脉粥样硬化性血栓形成卒中的易感基因，我们对2775例动脉粥样硬化性血栓形成卒中患者和2839名对照进行了大规模的病例对照研究和重复研究。通过对860例患者和860例年龄、性别匹配的对照的分析，发现ARHGEF10基因的单核苷酸多态(SNP)rs2280887与动脉粥样硬化血栓形成显著相关，即使在用置换检验调整多项检测后也是如此[未调整的P=1.2×10(-6)，优势比=1.80，95%可信区间=1.42-2.28]。这种关联在1915个独立病例和1979个对照中重复。随后的精细定位发现另外三个SNPs由于与rs2280887(r(2)>；0.95)的强连锁不平衡而表现出类似的关联。在对这四个高度相关的SNPs的功能分析中，通过荧光素酶分析和凝胶迁移率改变分析，我们发现rs4376531通过不同的Sp1结合亲和力影响ARHGEF10的转录活性。在小分子GTP酶活性测定中，我们发现ARHGEF10的一个基因产物特异性地激活了RhoA。一项基于人群的队列研究显示，携带rs4376531CC或CG的受试者增加了缺血性卒中的发生率(P=0.033，危险比=1.79，95%CI=1.0 5~3.0 4)。我们的数据表明，ARHGEF10的功能性SNP与动脉粥样硬化血栓形成的易感性有关。
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.