P2Y12基因多态性与急性缺血性卒中患者氯吡格雷抵抗和远期转归的相关性

Correlatiom of P2Y12 gene polymorphism with clopidogrel resistance and long-term outcome in patients with acute ischemic stroke

目的 探讨P2Y12基因多态性与急性缺血性卒中患者氯吡格雷抵抗和远期转归的相关性.方法 连续纳入2015年6月至2017年6月在南京江北人民医院神经内科住院的急性缺缺血性卒中患者.采用血栓弹力图仪测定血小板抑制率并评定氯吡格雷抵抗,采用聚合酶链反应测定P2Y12基因C34T 和G52T 多态性.在患者出院后12个月进行随访,主要终点为卒中复发、心肌梗死和因心脑血管事件死亡构成的联合终点.结果 共纳入214例患者,51例（23.8%）存在氯吡格雷抵抗,29例（13.4%）发生主要终点事件. C34T CC 基因型患者128例（59.8%）,CT＋TT 基因型86例（40.2%）,CT＋TT 基因型患者氯吡格雷抵抗的比例显著高于CC基因型患者（76.5%对28.8%;χ2=25.672,P=0.001）. G52T GG基因型患者131例（61.2%）,GT＋TT基因型83例（38.8%）,GT＋TT基因型患者氯吡格雷抵抗的比例与GG基因型患者无差异统计学意义（43.1%对37.4%;χ2=0.534,P=0.465）.多变量logistic回归分析显示,年龄[优势比（odds ratio, OR）1.064,95%可信区间（confidence interval, CI）1.009~1.115;P=0.021]、糖尿病（OR 3.773,95% CI 1.672~8.475;P=0.004）和C34T CT＋TT基因型（OR 9.087,95% CI 4.416~22.665;P=0.002）是氯吡格雷抵抗的独立危险因素. Cox比例风险模型分析显示,年龄[风险比（hazard ratio, HR）1.058,95% CI 1.001~1.121;P=0.049]、高血压（HR 3.105,95% CI 1.149~9.523;P=0.028）、高半胱氨酸（HR 1.101, 95% CI 1.020~1.190;P=0.014）和C34T CT＋TT基因型（HR 2.588,95% CI 1.121~5.967;P=0.026）是联合终点的独立危险因素.结论 急性缺血性卒中患者P2Y12基因C34T 多态性可能是氯吡格雷抵抗的危险因素,且与远期血管性事件复发风险独立相关.

Objective To investigate the correlations of P2Y12 gene polymorphisms with clopidogrel resistance and long-term outcome in patients with acute ischemic stroke. Methods From June 2015 to June 2017, consecutive patients with acute ischemic stroke admitted to the Department of Neurology, Nanjing Jiangbei People＇s Hospital were enrolled. Thromboelastography was used to measure platelet inhibition rate and assess clopidogrel resistance. Polymerase chain reaction was used to assay C34T and G52T polymorphisms of P2Y12 gene. The patients were followed up at 12 months after discharge. The primary outcome was combined outcome of stroke recurrence, myocardial infarction, and death due to cardiocerebrovascular events. Results A total of 214 patients were enrolled, 51 （23.8%） had clopidogrel re-sistance and 29 （13.4%） had major outcome events. One hundred twenty-eight （59.8%） patients were C34T CC genotype and 86 （40.2%） were CT＋TT genotype. The proportion of clopidogrel resistance in patients with CT＋TT genotype was significantly higher than that with CC genotype （ 76.5% vs.28.8%;χ2=25.672, P=0.001）. There were 131 patients （61.2%） with G52T GG genotype and 83 （38.8%） with GT＋TT genotype. There was no significant difference in the proportion of clopidogrel resistance between the GT＋TT genotype and the GG genotype （43.1% vs.37.4%; χ2=0.534, P=0.465）. Multiple logistic regression analysis indicated that age （odds ratio [OR] 1.064, 95%confidence interval [CI] 1.009-1.115;P=0.021）, diabetes （ OR 3.773, 95%CI 1.672-8.475; P=0.004）, and C34T CT＋TT genotype （ OR 9.087, 95%CI 4.416-22.665; P=0.002） were the independent risk factors fot clopidogrel resistance. Cox proportional hazards model analysis showed that age （Hazard ratio [HR] 1.058, 95%CI 1.001-1.121; P=0.049）, hypertension （ HR 3.105, 95%CI 1.149-9.523; P=0.028）, homocysteine （ HR 1.101, 95%CI 1.020-1.190; P=0.014）, and C34T CT＋TT genotype （ HR 2.588, 95%CI 1.121-5.967; P=0.026） were independent risk factors for the composite outcome. Conclusion C34T polymorphism of P2Y12 gene in patients with acute ischemic stroke may be a risk factor for clopidogrel resistance and is independently associated with the risk of long-term recurrence of vascular events.