Paraoxonase 1 Q192R Variant and Clopidogrel Efficacy

Abstract

Clopidogrel, in combination with aspirin, is the standard of care for preventing ischemic cardiovascular events in patients with coronary artery disease, especially those who undergo percutaneous coronary intervention (PCI). Despite its widespread use, significant interindividual variability in clopidogrel response is consistently observed, and recent studies have suggested that as much as 70% of this variability can be attributed to genetic factors.1,2 Article see p 250 Clopidogrel is a thienopyridine prodrug that once activated, exerts its antiplatelet effect by irreversibly binding to the P2Y12 receptor on the surface of platelets inhibiting ADP-stimulated platelet aggregation. Clopidogrel activation requires a 2-step conversion by hepatic enzymes, most notably CYP2C19, whereas esterases (eg, carboxylesterase 1 and carboxylesterase 2) lead to the production of biologically inactive carboxylic acid derivatives.3 Common loss-of-function variants in CYP2C19 are associated with lower active metabolite levels, higher residual on-clopidogrel ADP-stimulated platelet aggregation, and poorer cardiovascular outcomes.3 However, this variant explains only ≈12% of the variation in platelet response to clopidogrel, leaving most of the heritable variation unknown. Recently, Bouman and colleagues4 observed through in vitro studies that paraoxonase 1 (PON1) was the major enzyme in converting 2-oxo-clopidogrel to the active thiol metabolite. Moreover, they reported that a common missense variant in PON1 , Q192R, was a major determinant of clopidogrel efficacy, accounting for nearly 70% of the variability in ADP-stimulated platelet aggregation postclopidogrel treatment. 192Q PON1 had lower hydrolysis efficiency for 2-oxo-clopidogrel compared to 192R PON1 in microsomal preparations, and clopidogrel-treated PCI patients homozygous for the 192Q allele had a significantly higher rate of stent thrombosis compared with patients carrying at least 1 copy of the 192R allele. Curiously, no effect of the well-described CYP2C19 *2 loss-of-function variant on clopidogrel response was observed in the same patient sample. In the past year, our group and …