血管内皮细胞生长因子受体基因变异297Val→Ile与受体功能及脑卒中易感性

Assodation of variants in the vascular endothelial growth factor receptor 2 gene and the risk of hemorrhagic stroke

目的探讨血管内皮细胞生长因子受体（VEGFR-2）基因的编码区变异对受体功能的影响及与脑卒中患病风险的关系。方法利用多中心病例-对照研究，在1849例脑卒中患者（血栓形成性脑梗死812例，腔隙性脑梗死530例，脑出血507例）和1798例对照人群中检测VEGFR-2基因编码区变异rs2305948（Val297Ile）与脑卒中易感性的关联，并在另一个独立的病例-对照研究（327例脑卒中和327例对照）中进行验证。放射性受体配体结合实验测定基因变异对VEGFR-2与配基VEGF亲和能力的改变。结果VEGFR-2基因变异297Ile携带者频率在脑出血组显著高于对照组[脑出血组：Val／Ile，155（30．6％）；Ile／Ile，16（3．2％）；对照组：Val/Ile，351（19．5％）；Ile／lle，18（1．0％）；P〈0．01]，与脑出血的高发病风险相关（OR 2．25；95％CI 1．70—2．96；P〈0．01），验证研究亦得到相似结果。常见等位基因297Val被替换为297Ile时，VEGFR-2与配基VEGF的平衡解离常数显著增加[分别为（87±9）pmol/L和（195±36）pmol/L，P〈0．01]。结论VEGFR-2基因变异297Ile降低该受体与配基的亲和能力，并与脑出血的高发病风险相关。其分子机制可能是由于VEGF／VEGFR-2信号通路下调，引起血管内皮细胞的稳态和完整性受损，在血压升高等情况下导致血管易破裂、出血。

Objective To assess whether variants in the vascular endothelial growth actor receptor 2 （VEGFR-2） gene confer susceptibility to stroke risk. Methods Association between gene variant rs2305948 （Va1297Ile） and the risk of stroke was investigated 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, and then replicated in the second independent stroke study （327 cases and 327 controls）. The effect of Va1297Ile on the binding ability of VEGFR-2 to VEGF was determined by a radioligand binding assay. Results The frequencies of carriers with variant 297Ile were significantly higher in patients with hemorrhagic stroke than in controls [ 297VaL/Ile ： 155 （30.6%） versus 351 （ 19.5% ）, 297Ile/Ile： 18（3.2% ） versus 16（ 1.0% ） ; P 〈0.01 ]. The variant 297Ile was significantly associated with increased risk of hemorrhagic stroke （ odds ratio 2.25, 95% confidence interval 1.70-2.96 ; P 〈0.01 ）, and replication in the second stroke study obtained similar results. The substitution of Val to lie at the amino acid residue 297 led to an increased equilibrium dissolved constant between VEGF and its receptor VEGFR-2 [297Val （87 ±9） pmol/L versus 297Ile （195 ±36） pmol/L, P 〈0.01 ]. Conclusions The VEGFR-2 gene variants may serve as novel genetic markers for the risk of hemorrhagic stroke.