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The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response.

ABSTRACT: Carboxylesterase 1 (CES1) is the primary enzyme responsible for converting clopidogrel into biologically inactive carboxylic acid metabolites.We genotyped a functional variant in CES1, G143E, in participants of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) study (n=566) and in 350 patients with coronary heart disease treated with clopidogrel, and carried out an association analysis of bioactive metabolite levels, on-clopidogrel ADP-stimulated platelet aggregation, and cardiovascular outcomes.The levels of clopidogrel active metabolite were significantly greater in CES1 143E-allele carriers (P=0.001). Consistent with these findings, individuals who carried the CES1 143E-allele showed a better clopidogrel response as measured by ADP-stimulated platelet aggregation in both participants of the PAPI study (P=0.003) and clopidogrel-treated coronary heart disease patients (P=0.03). No association was found between this single nucleotide polymorphism and baseline measures of platelet aggregation in either cohort.Taken together, these findings suggest, for the first time, that genetic variation in CES1 may be an important determinant of the efficacy of clopidogrel.

SUBMITTER: Lewis JP

PROVIDER: S-EPMC3682407 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response.

Lewis Joshua P JP Horenstein Richard B RB Ryan Kathleen K O'Connell Jeffrey R JR Gibson Quince Q Mitchell Braxton D BD Tanner Keith K Chai Sumbul S Bliden Kevin P KP Tantry Udaya S US Peer Cody J CJ Figg William D WD Spencer Shawn D SD Pacanowski Michael A MA Gurbel Paul A PA Shuldiner Alan R AR

Pharmacogenetics and genomics 20130101 1

<h4>Introduction</h4>Carboxylesterase 1 (CES1) is the primary enzyme responsible for converting clopidogrel into biologically inactive carboxylic acid metabolites.<h4>Methods</h4>We genotyped a functional variant in CES1, G143E, in participants of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) study (n=566) and in 350 patients with coronary heart disease treated with clopidogrel, and carried out an association analysis of bioactive metabolite levels, on-clopidogrel ADP-stimulated plat ...[more]

PMID: 23111421

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Project description: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 (? = -5.24, P = 3.0 × 10(-9) and ? = -5.36, P = 3.3 × 10(-14) , respectively) and posttreatment ADP-stimulated platelet aggregation (? = 7.55, P = 2.9 × 10(-16) and ? = 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 (? = 1.57, P = 0.04 and ? = -1.98, P = 0.01, respectively) but not after (? = 0.40, P = 0.59 and ? = -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.

Dataset Information

The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response.

Publications

The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response.

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