易感基因MicroRNA结合区位点多态性及使用口服避孕药与女性脑卒中发病风险的关联研究

Single nucleotide polymorphisms in MicroRNA binding sites of susceptibility genes and association of oral contraceptive use with risk of stroke in Chinese women

目的 探讨使用复方口服避孕药（COC）、易感基因MicroRNA（miRNA）结合区位点多态性及其联合作用对女性脑卒中发病风险的影响. 方法 自1997年7月至2009年6月在江苏太仓、如东两地区的女性避孕药和宫内节育器使用队列中选择453例女性脑卒中患者作为脑卒中组,其中出血性脑卒中165例,缺血性脑卒中285例,未分型脑卒中3例;另选取919名年龄、地区相匹配的女性作为对照组.收集2组研究对象的临床资料,PCR TaqMan探针技术检测肾素-血管紧张素-醛固酮（RAAS）通路基因miRNA结合区4个单核苷酸多态性（SNPs）位点的基因型.应用非条件Logistic回归、叉生分析各基因型、使用COC及其联合作用对脑卒中发病的影响. 结果 脑卒中组患者使用COC、高血压、高脂血症及脑卒中家族史的比例均高于对照组,差异有统计学意义（P＜0.05）;miR-155的靶基因AGTR1 rs5186位点的遗传变异（A＞C）是出血性脑卒中发生的危险因素;与不使用COC且不携带风险基因（rs5186 AA）的个体相比,不携带风险基因但使用COC患出血性脑卒中的风险增加0.71倍（OR=1.71,95％CI：1.18～2.48）,携带风险基因同时使用COC患出血性脑卒中的风险增加1.81倍（OR=2.81,95％CI：1.40～5.64）,不携带风险基因但使用COC的个体患脑卒中的风险增加0.32倍（OR=1.32,95％CI：1.04～1.68）. 结论 AGTR1基因rs5186位点的遗传变异与出血性脑卒中的发病相关,且该遗传变异与COC使用的联合作用可以增加出血性脑卒中的发病风险.

Objective To investigate the associations of stroke with oral contraception （COC） use,single nucleotide polymorphisms （SNPs） in miRNA binding sites of susceptibility genes and their joint effects in women.Methods Four hundred and fifty-three female patients with stroke,accepted COC or intrauterine device from two regions from July 1997 to June 2009,were chosen as stroke group,including 165 with hemorrhagic stroke,285 with infarct stroke and 3 with indeterminate stroke.The ageand region-matched controls （n=919） were recruited from the female cohort.The clinical data of these two groups were collected.Genotyping of 4 SNPs in miRNA binding sites in the reninangiotensin-aldosterone system （RAAS） genes was performed by polymerase chain reaction assay with Taqman probes.Unconditioned Logistic regression and dichotomy analyses were employed to analyze the influences of COC use and each genotype in stroke.Results As compared with the control group,the stroke group had significantly higher ratios of COC use,hypertension,hyperlipidemia and family history of stroke （P〈0.05）; as compared with the wild-type homozygote rs5186AA,both AC genotype and combined genotype AC/CC of rs5186 were associated with a significant risk effect for hemorrhagic stroke （OR=1.83,95%CI：1.10-2.97;OR=1.74,95%CI：1.06-2.87）.As compared with non-users without genetic variant,COC user without genetic variant increased the risk of hemorrhagic stroke by 0.71 fold （OR=1.71,95%CI：1.18-2.48）,and COC use combined with genetic variant of rs5186 increased the risk of hemorrhagic stroke by 1.81 fold （OR=2.81,95%CI：1.45-5.64）; as compared with non-users without genetic variant,COC user without genetic variant increased the stroke risk by 0.32 fold （OR=1.32,95%CI：1.04-1.68）.Conclusion The variant of rs5186（A〉C） of angiotensin Ⅱ typer 1 receptor gene is positively associated with risk of hemorrhagic stroke,and COC use combined with this genetic variant significantly increases the risk of hemorrhagic stroke.