Background— The cytochrome P450 (CYP) 2C19 isoenzyme plays an important role in clopidogrel metabolization. A recently explored CYP2C19 * 17 allelic variant has been linked to increased transcriptional activity, resulting in extensive metabolization of CYP2C19 substrates, which may lead to an enhanced platelet response to clopidogrel treatment. The aim of this study was to assess the impact of CYP2C19 * 17 on ADP-induced platelet aggregation, the risk of bleeding, and stent thrombosis in clopidogrel-treated patients undergoing percutaneous coronary intervention. Methods and Results— The study population included 1524 patients undergoing percutaneous coronary intervention after pretreatment with 600 mg clopidogrel. Genotypes were determined with a TaqMan assay. ADP-induced platelet aggregation was assessed on a Multiplate analyzer. The primary clinical safety end point was the 30-day incidence of bleeding defined according to Thrombolysis in Myocardial Infarction criteria, and the primary clinical efficacy end point was the 30-day incidence of stent thrombosis. For both heterozygous (*wt/*17; n=546) and homozygous (*17/*17; n=76) allele carriers, significantly lower ADP-induced platelet aggregation values were found compared with wild-type homozygotes (*wt/*wt; n=902; P =0.039 and P =0.008, respectively). CYP2C19 * 17 allele carriage was significantly associated with an increased risk of bleeding; the highest risk was observed for CYP2C19 * 17 homozygous patients ( P =0.01, χ 2 test for trend). Multivariate analysis confirmed the independent association of CYP2C19 * 17 allele carriage with platelet aggregation values ( P <0.001) and the occurrence of bleeding ( P =0.006). No significant influence of CYP2C19 * 17 on the occurrence of stent thrombosis was found ( P =0.79). Conclusions— CYP2C19 * 17 carrier status is significantly associated with enhanced response to clopidogrel and an increased risk of bleeding.

Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J Thromb Haemost 2010; 8: 1685-93.Summary. 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.