Abstract 11255: PON1 Q192R (rs662) Genetic Variant and Response to Clopidogrel and Prasugrel
Background: Clopidogrel and prasugrel are pro-drugs requiring biotransformation into active metabolites. Multiple studies have validated the relationship between loss-of-function alleles in the CYP2C19 gene and the pharmacological and clinical response to clopidogrel. Recently, a study has proposed that a functional genetic variant (Q192R, rs662) in the paraoxonase gene (PON1) significantly enhances the biotransformation of clopidogrel (Nat Med 2011); replication of this association for clopidogrel and evaluation of its impact on prasugrel are needed.
Methods: We genotyped PON1 rs662 in 275 healthy subjects treated with clopidogrel or prasugrel and tested the association with plasma concentrations of active drug metabolites and change in maximal platelet aggregation. We are also genotyping this variant in a separate cohort of ∼3,000 patients with an ACS treated with clopidogrel or prasugrel in the TRITON-TIMI 38 trial.
Results: In healthy subjects, the genotypes for rs662 were: 37% A/A, 45% A/G, and 18% G/G. In contrast to the previous observation, among clopidogrel-treated subjects, there were no significant associations between rs662 and plasma concentrations of active drug metabolite (P=0.62) or change in platelet aggregation (P=0.51) for loading or maintenance dosing (Figure). Likewise, among prasugrel-treated subjects, there were no significant associations between rs662 and plasma concentrations of active drug metabolite (P=0.88) or change in platelet aggregation (P=0.97) for loading or maintenance dosing (Figure). Data on the association of rs662 and cardiovascular clinical outcomes will be available for presentation in November 2011.
Conclusions: In contrast to prior observations, in the present study, the Q192R (rs662) genetic variant in PON1 was not associated with the pharmacological response to clopidogrel, nor was it associated with the response to prasugrel.
- © 2011 by American Heart Association, Inc.