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Clopidogrel is an antiplatelet prodrug that is recommended to reduce the risk of recurrent thrombosis in coronary artery disease (CAD) patients. Paraoxonase 1 (PON1) is suggested to be a rate-limiting enzyme in the conversion of 2-oxo-clopidogrel to active thiol metabolite with inconsistent results. Here, we sought to determine the associations of  CYP2C19  and  PON1  gene polymorphisms with clopidogrel response and their role in ADP-induced platelet aggregation. Clopidogrel response and platelet aggregation were determined using Multiplate aggregometer in 211 patients with established CAD who received 75 mg clopidogrel and 75–325 mg aspirin daily for at least 14 days. Polymorphisms in  CYP2C19  and  PON1  were genotyped and tested for association with clopidogrel resistance. Linkage disequilibrium (LD) and their epistatic interaction effects on ADP-induced platelet aggregation were analysed. The prevalence of clopidogrel resistance in this population was approximately 33.2% (n = 70). The frequencies of  CYP2C19 *2 and *3 were significantly higher in non-responder than those in responders. After adjusting for established risk factors,  CYP2C19 *2 and *3 alleles independently increased the risk of clopidogrel resistance with adjusted ORs 2.94 (95%CI, 1.65–5.26; p<0.001) and 11.26 (95%CI, 2.47–51.41; p = 0.002, respectively). Patients with *2 or *3 allele and combined with smoking, diabetes and increased platelet count had markedly increased risk of clopidogrel resistance. No association was observed between  PON1  Q192R and clopidogrel resistance (adjusted OR = 1.13, 95%CI, 0.70–1.82; p = 0.622). Significantly higher platelet aggregation values were found in  CYP2C19 *2 and *3 patients when compared with *1/*1 allele carriers (p = 1.98×10 −6 ). For  PON1  Q192R genotypes, aggregation values were similar across all genotype groups (p = 0.359). There was no evidence of gene-gene interaction or LD between  CYP2C19  and  PON1  polymorphisms on ADP-induced platelet aggregation. Our findings indicated that only  CYP2C19 *2 and *3 alleles had an influence on clopidogrel resistance. The risk of clopidogrel resistance increased further with smoking, diabetes, and increased platelet count.

plos one

Effects of Cytochrome P450 2C19 and Paraoxonase 1 Polymorphisms on Antiplatelet Response to Clopidogrel Therapy in Patients with Coronary Artery Disease