Unraveling the Pharmacogenetics of Clopidogrel

Clopidogrel forms a cornerstone in the treatment of patients undergoing coronary stenting. Although the clinical effectiveness of clopidogrel has been shown repeatedly in large clinical trials, there appears to be a large interindividual response variability that influences the risk of atherothrombotic events.1,2 Studies3,4 have shown that differences in the plasma concentration of the active metabolite of clopidogrel are an important determinant of its antiplatelet effect. Although several environmental factors influence the formation of the active metabolite, most variation appears to be genetic.5 Numerous studies5–7 have shown that polymorphisms in genes encoding the cytochrome (CYP) p450 system, especially CYP2C19, influence bioactivation of clopidogrel and, hence, the risk of cardiovascular events, especially stent thrombosis. Still, polymorphic variation in CYP2C19 seems to explain only 5% to 11% of the response variability to clopidogrel, leaving variation in bioactivation of clopidogrel largely unexplained.5,8Article see p 422A new player in the pharmacogenetics of clopidogrel was introduced by Bouman et al,9 who identified paraoxonase-1 (PON1) as a major determinant of the bioactivation and clinical efficacy of clopidogrel in a series of elegant experiments and clinical studies among subjects from European descent. This hepatic esterase is associated with high-density lipoprotein and has antioxidative effects on low-density lipoprotein and macrophages. Bouman et al identified PON1 as the crucial enzyme for the bioactivation of clopidogrel, with its common Q192R polymorphism determining the rate of active thiol metabolite formation. In a case-cohort study among 41 cases with stent thrombosis and 71 control subjects, the Q allele was dose-dependently associated with lower PON1 activity and active metabolite concentrations in plasma, reduced platelet inhibition, and a higher risk of stent thrombosis. Q192R explained >70% of the response variability to clopidogrel. The authors corroborated their findings in a …