The CYP2C19*17 variant is not independently associated with clopidogrel response

Abstract

Cytochrome P450 2C19 (CYP2C19) is the principal enzyme responsible for converting clopidogrel into its active metabolite, and common genetic variants have been identified, most notably CYP2C19*2 and CYP2C19*17, that are believed to alter its activity and expression, respectively. We evaluated whether the consequences of the CYP2C19*2 and CYP2C19*17 variants on clopidogrel response were independent of each other or genetically linked through linkage disequilibrium (LD). We genotyped the CYP2C19*2 and CYP2C19*17 variants in 621 members of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and evaluated the effects of these polymorphisms singly and then jointly, taking into account LD, on clopidogrel prodrug level, clopidogrel active metabolite level, and adenosine 5'-diphosphate (ADP)-stimulated platelet aggregation before and after clopidogrel exposure. The CYP2C19*2 and CYP2C19*17 variants were in LD (|D'|=1.0; r(2) =0.07). In association analyses that did and did not account for the effects of CYP2C19*17, CYP2C19*2 was strongly associated with levels of clopidogrel active metabolite (β=-5.24, P=3.0×10(-9) and β=-5.36, P=3.3×10(-14) , respectively) and posttreatment ADP-stimulated platelet aggregation (β=7.55, P=2.9×10(-16) and β=7.51, P=7.0×10(-15) , respectively). In contrast, CYP2C19*17 was marginally associated with clopidogrel active metabolite levels and ADP-stimulated platelet aggregation before (β=1.57, P=0.04 and β=-1.98, P=0.01, respectively) but not after (β=0.40, P=0.59 and β=-0.13, P=0.69, respectively) adjustment for the CYP2C19*2 variant. Stratified analyses of CYP2C19*2/CYP2C19*17 genotype combinations revealed that CYP2C19*2, and not CYP2C19*17, was the primary determinant in altering clopidogrel response. Our results suggest that CYP2C19*17 has a small (if any) effect on clopidogrel-related traits and that the observed effect of this variant is due to LD with the CYP2C19*2 loss-of-function variant.