经皮冠状动脉介入患者氯吡格雷治疗后血小板高反应性的危险因素筛查及基因多态性研究

Risk factors of high on-treatment platelet reactivity to clopidogrel after percutaneous coronary intervention and the association with gene polymorphism

目的探讨经皮冠状动脉介入(PCI)患者氯吡格雷治疗后血小板高反应性(HTPR)的危险因素,分析基因多态性的特点以及与HTPR的关系。方法选取2017年1月至2019年1月在湖南省人民医院成功完成PCI术的冠状动脉粥样硬化性心脏病患者558例,给予标准双联抗血小板药物阿司匹林和氯吡格雷治疗。行血栓弹力图血小板功能检测,分为HTPR组(血小板聚集抑制率≤30%)和非HTPR组(血小板聚集抑制率>30%)。采用MassARRAY法检测与氯吡格雷代谢和作用靶点相关基因的单核苷酸多态性。采用多因素Logistic回归模型分析影响HTPR发生的危险因素。结果根据血栓弹力图检测结果,83例(14.9%)患者发生HTPR。共存基因多态性患者的HTPR发生率高于单个基因多态性患者[22.4%(60/268)比13.8%(23/167),P=0.026]。Logistic回归分析结果显示,性别(女性)(比值比=2.023)、糖尿病史(比值比=2.815)、低密度脂蛋白胆固醇升高(比值比=3.012)、共存基因多态性(比值比=2.451)以及CYP2C9基因rs1057910位点的基因型频率分布(比值比=2.985)是HTPR发生的独立危险因素,而CYP3A4基因rs^2242480位点基因型分布是HTPR发生的独立保护因素(比值比=0.693)。结论女性、糖尿病、高低密度脂蛋白胆固醇水平、多个基因多态性共存可能是导致PCI术患者氯吡格雷治疗后发生HTPR的危险因素。

Objective To explore the risk factors of high on-treatment platelet reactivity(HTPR)to clopidogrel and the association with gene polymorphism in patients undergoing percutaneous coronary intervention(PCI).Methods Totally 558 patients with coronary atherosclerotic heart disease who had PCI in Hunan People’s Hospital from January 2017 to January 2019 were enrolled.Standard double antiplatelet treatment with aspirin and clopidogrel was performed in all patients.According to the inhibition of platelet aggregation rate(IPA)measured by thrombelastogram,the patients were divided into HTPR group(IPA≤30%)and non-HTPR group(IPA>30%).Single nucleotide polymorphisms(SNPs)of genes associated with clopidogrel metabolism were detected by MassARRAY genotyping system.Risk factors of HTPR to clopidogrel were analyzed by multivariate logistic regression.Results There were 83 patients(14.9%)having HTPR.Incidence of HTPR in patients with coexisting SNPs was lower than that in patients with single SNP[22.4%(60/268)vs 13.8%(23/167),P=0.026].Logistic regression showed that female(odds ratio=2.023),diabetes(odds ratio=2.815),elevated low density lipoprotein cholesterol(LDL-C)level(odds ratio=3.012),coexisting SNPs(odds ratio=2.451)and cytochrome P4502 C9 rs1057910 SNP(odds ratio=2.985)were independent risk factors of HTPR;CYP3 A4 rs^2242480 SNP was an independent protective factor of HTPR(odds ratio=0.693).Conclusion Female,diabetes,high LDL-C level and coexisting SNPs may be risk factors of HTPR to clopidogrel after PCI.