CYP2C19 基因多态性与冠心病危险因素对氯吡格雷抵抗的影响

目的:观察细胞色素P450系统药物代谢酶CYP2C19基因多态性以及相关临床因素对氯吡格雷抵抗的影响。方法:选择2010年11月至2011年5月我科拟行PCI术治疗的冠心病患者共145例,均给予氯吡格雷300mg负荷剂量,75mg维持剂量。①通过流式细胞仪检测血管舒张因子刺激酸磷蛋白血小板反应性指数VASP PRI(以VASP PRI≥50%,定义为氯吡格雷抵抗)分为氯吡格雷抵抗组和氯吡格雷反应组。②检测入选患者的药物代谢酶CYP2C19的基因型;根据不同等位基因功能缺失,分为快代谢基因型(*1/*1)、中间代谢基因型(*1/*2、*1/*3)和慢代谢基因型(*2/*2、*2/*3、*3/*3)。③观察CYP2C19基因型及相关临床危险因素对氯吡格雷反应性的影响,④观察氯吡格雷抵抗与临床不良终点事件主要临床不良终点事件心源性死亡、再发心肌梗死、靶病变再次血运重建术(TLR)]和次要临床终点事件(支架内血栓形成、脑血管意外、大出血)之间的相关性。结果:检测出氯吡格雷抵抗的患者31例,其发生率为20.67%;检测出CYP2C19慢代谢基因型携带患者19例,所占比例为12.67%。慢代谢基因型患者与(快代谢基因型+中间代谢基因型患者)之间VASP PRI比为(49.20±8.45)%VS(44.17±5.41)%,P<0.05,氯吡格雷抵抗发生率之比为35.49%(n=11)VS16.81%(n=20),P<0.05。多元回归分析提示CYP2C19慢代谢基因型(OR:4.43;95%CI:3.28-8.37,P<0.05)和2型糖尿病(OR:2.76;95%CI:2.13-6.14;P<0.05)是氯吡格雷抵抗的两种危险因素。临床随访结果显示氯吡格雷抵抗组与氯吡格雷反应组主要临床不良终点事件的发生率比为6.45%(n=2)vs2.63%(n=3),P<0.05。结论:携带CPY2C19慢代谢基因型和患有2型糖尿病是导致氯吡格雷抵抗的两种重要的危险因素,氯吡格雷抵抗的发生增加了临床不良终点事件的风险。

Effect of CYP2C19 Polymorphism and Risk Factors for Coronary Artery Disease on Clopidogrel Resistance

Objective: To investigate the impact of cytochrome P450 2C19(CYP2C19) polymorphism and clinical variables related to coronary artery disease on antiplatelet effect of clopidogrel.Methods: From November 2010 to May 2011,146 patients undergoing percutaneous coronary intervention in our department were enrolled and received 300 mg loading dose and 75 mg daily maintenance dose of clopidogrel.Clopidogrel resistance was defined as platelet reactivity index(PRI) ≥ 50%,which was measured by flow cytometric assessment of phosphorylation status of vasodilator-stimulated phosphoprotein(VASP).Genotyping of CYP2C19 determined by TaqMan polymerase chain reaction was classified as: extensive(*1/*1) intermediate(*1/*2、*1/*3)and poor metabolizer(*2/*2,*2/*3,*3/*3).The predictive value of the CYP2C19 polymorphism and baseline risk factors for an insufficient antiplatelet response of clopidogrel was analyzed by multivariable regression analysis and classification and regression trees analysis.The relationship of clopidogrel resistance with adverse cardiovascular events was evaluated by logistic regression analysis.Results: Clopidogrel resistance was present in 20.67% patients.The proportion of poor metabolizer was 12.67%,which had significantly higher on-treatment platelet reactivity than extensive and intermediate metabolizers(mean VASP PRI,49.20±8.45 vs 44.17±5.41;P<0.05).Poor metabolizer came up with a higher incidence of clopidogrel resistance than the other two genotypes(35.49% vs 16.81%;P<0.05).Major independent predictors for an insufficient antiplatelet response to clopidogrel were CYP2C19 genotype status(OR: 4.43;95% CI: 3.28-8.37;P<0.05) and diabetes mellitus(OR: 2.76;95% CI: 2.13-6.14;P<0.05).The clinical follow-up revealed higher incidence of MACE(6.45% vs 2.63%,P<0.05) in clopidogrel resistance patients.Conclusion: Clopidogrel resistance was closely associated with CYP2C19 genotype and nongenetic risk factor,diabetes mellitus,which may substantially improve the prediction of clinical outcomes for patients after PCI.