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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 investigate the relationship between the promoter region polymorphism of vascular endothelial growth factor receptor (VEGFR-2) gene and the risk of stroke. Methods: A multicentre case-control study of 1849 stroke patients (thrombotic cerebral infarction 812 cases, lacunar infarction 530 cases, 507 cases of cerebral hemorrhage) and 1798 cases of control VEGFR-2 gene promoter State -604T / C frequency distribution, Logistic regression model analysis of polymorphisms and stroke correlation. The luciferase activity was assayed and the effect of the mutant polymorphism on the transcriptional activity of VEGFR-2 gene was analyzed. Results: The frequencies of polymorphisms -604TC and CC genotypes of VEGFR-2 gene in cerebral infarction group were significantly lower than those in control group (TC36.7%, CC8.4%; control group: TC41.8%, CC10.3 %; P <0.01). The frequency of C allele in cerebral infarction group was significantly lower than that in control group (26.7% vs 31.2%, P <0.01). The -604C allele was associated with a lower risk of developing cerebral infarction (OR: 0.78; 95% CI: 0.65-0.95; P <0.05). Polymorphic-604C reduced the transcriptional activity of this gene by 2.93-fold as compared to wild-type-604T. Conclusion: VEGFR-2 gene mutation -604C reduces the transcriptional activity of VEGFR-2 gene and is associated with the decreased risk of cerebral infarction. Its molecular mechanism may be due to the VEGF / VEGFR-2 signaling pathway downregulation of neovascularization in the plaque to delay or reduce the progress of atherosclerosis.