Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy
Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy
复制标题
DOI：
10.1111/j.1538-7836.2010.03921.x
复制
发表时间：
2010-08-01
影响因子：
10.4
通讯作者：
Kastrati, A.
中科院分区：
文献类型：
--
作者：
Sibbing, D.;Gebhard, D.;Kastrati, A.
背景：由于细胞色素P450的等位基因突变导致酶功能的完全丧失，以及细胞色素P450的突变导致酶活性的增强和底物的广泛代谢，最近发现了两种常见的细胞色素P450基因突变。目前，这两种变异体对慢性氯吡格雷抗血小板效应的单独和交互影响尚不清楚。目的：本研究的目的是评估*2和*17对接受氯吡格雷维持治疗的患者的氯吡格雷反应性的单独和交互影响。方法：符合研究条件的986例患者接受阿司匹林和氯吡格雷的冠脉支架相关慢性治疗。用多平板分析仪(AU*min)测定ADP诱导的血小板聚集率，用TaqMan法检测ADP诱导的血小板聚集率。结果：携带至少一个*2等位基因携带者的血小板聚集值显著高于纯合子野生型等位基因携带者(P<；0.001)。*17等位基因携带者的血小板聚集值显著低于野生型纯合子患者(P=0.01)。观察到两种变异的基因剂量效应，在纯合子患者中发现突变等位基因(*2或*17)的显著效应。在两个变异体对血小板聚集值的交互作用中，血小板聚集值从(+)*17/(-)*2患者逐渐增加，其中位数为207AU*min，到(-)*17/(-)*2、(+)*17/(+)*2和(-)*17/(+)*2患者的最高值(中位数为309AU*min)(P<；0.001)。结论：*2和*17等位基因携带者是慢性氯吡格雷抗血小板疗效的独立预测因子。
Background: With the cytochrome P450 CYP2C19*2 (*2) allelic variant resulting in complete loss of enzyme function and the CYP2C19*17 (*17) variant being linked to increased transcriptional activity with extensive metabolism of CYP2C19 substrates, two common variants of the CYP2C19 gene have been explored recently. Currently, the isolated and interactive impacts of both variants on the antiplatelet effects of chronic clopidogrel therapy are unknown. Objectives: The aim of this study was to assess the isolated and interactive impacts of *2 and *17 on clopidogrel responsiveness in patients under clopidogrel maintenance treatment. Methods: Patients (n = 986) eligible for this study were under therapy with coronary stent-related chronic treatment with aspirin and clopidogrel. The ADP-induced platelet aggregation was measured on a Multiplate analyzer (in AU*min), and genotypes were determined with a TaqMan assay. Results: Platelet aggregation values were significantly higher in carriers of at least one *2 allele than in homozygous wild-type allele carriers (P < 0.001). For *17, platelet aggregation values were significantly lower in carriers of at least one *17 allele than in homozygous wild-type patients (P = 0.01). A gene-dose effect was observed for both variants, with a pronounced effect of the mutant allele (*2 or *17) in homozygous patients being seen. For the interactive effect of both variants on platelet aggregation values, a gradual increase in platelet aggregation values was observed from (+)*17/(-)*2 patients, who exhibited the lowest values (median of 207 AU*min) to (-)*17/(-)*2, (+)*17/(+)*2 and (-)*17/(+)*2 patients, who exhibited the highest values (median of 309 AU*min) (P < 0.001). Conclusions: *2 and *17 allele carriage are independent predictors for the antiplatelet effect of chronic clopidogrel therapy.