血管内皮细胞生长因子受体基因启动子区多态性与脑卒中的关系

Association of Polymorphism in Vascular Endothelial Growth Factor Receptor 2 Gene and Risk of Stroke

目的:探讨血管内皮细胞生长因子受体(VEGFR-2)基因启动子区多态性与脑卒中患病风险的关系。方法:利用多中心病例—对照研究,对1849例脑卒中患者(血栓形成性脑梗塞812例,腔隙性脑梗塞530例,脑出血507例)和1798例对照检测VEGFR-2基因启动子多态-604T/C的频率分布,Logistic回归模型分析多态与脑卒中的相关性。测定荧光素酶活性,分析突变型多态对VEGFR-2基因转录活性的影响。结果:VEGFR-2基因多态-604TC和CC基因型频率在脑梗塞组显著低于对照组(脑梗塞者:TC36.7%,CC8.4%;对照组:TC41.8%,CC10.3%;P<0.01),脑梗塞者C等位基因频率显著低于对照组(26.7%比31.2%,P<0.01),均有显著性差异。-604C等位基因与脑梗塞的低发病风险相关(OR:0.78;95%CI:0.65～0.95;P<0.05)。多态-604C与野生型-604T相比,降低该基因的转录活性2.93倍。结论:VEGFR-2基因启动子变异-604C降低该基因的转录活性,并与降低脑梗塞的发病风险相关。其分子机制可能是由于VEGF/VEGFR-2信号通路下调,降低斑块内的新生血管化程度,从而延迟或减轻动脉粥样硬化的进展。

Objective：To assess whether polymorphisms in the promoter region of vascular endothelial growth factor receptor 2 （ VEGFR- 2）gene can confer susceptibility to stroke risk. Methods：Distribution of frequencies of polymorphism -604T/C was determined in a multi-center case-control study, which comprised of 1849 patients with stroke （812 cerebral atherothrombosis,530 lacunar infarction, and 507 intracerebral hemorrhage） and 1798 controls. Multivariate logistic regression model was used to assess the association with stroke risk. The effect of-604T/ C on VEGFR-2 promoter activity was determined by luciferase reporter assays. Results：The frequencies of -604CC and TC genotypes were significantly lower in patients with thrombosis （TC 36.7% , CC 8.4% ）than in controls （TC 41.8% ,CC 10. 3% ） （P = 0. 004）, and -604C allele was associated with decreased risk for athero- thrombotic stroke （ OR：0. 78 ;95% CI：0. 65-0. 95 ; P = 0. 025 ）. Moreover,-604C showed a significantly lower luciferase activity by 2.93 folds compared to the wild-type T allele（ P 〈0. 001 ）. Conclusions：Polymorphism -604T/C in the promoter of VEGFR-2 gene contributes to a decreased risk for atherothrombotic stroke,probably through a down-regulated angiogenesis effect of VEGF in the progress of atherosclerosis.