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

Published

Journal Article

INTRODUCTION: Carboxylesterase 1 (CES1) is the primary enzyme responsible for converting clopidogrel into biologically inactive carboxylic acid metabolites. METHODS: 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. RESULTS: 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. CONCLUSION: Taken together, these findings suggest, for the first time, that genetic variation in CES1 may be an important determinant of the efficacy of clopidogrel.

Full Text

Duke Authors

Cited Authors

  • Lewis, JP; Horenstein, RB; Ryan, K; O'Connell, JR; Gibson, Q; Mitchell, BD; Tanner, K; Chai, S; Bliden, KP; Tantry, US; Peer, CJ; Figg, WD; Spencer, SD; Pacanowski, MA; Gurbel, PA; Shuldiner, AR

Published Date

  • January 2013

Published In

Volume / Issue

  • 23 / 1

Start / End Page

  • 1 - 8

PubMed ID

  • 23111421

Pubmed Central ID

  • 23111421

Electronic International Standard Serial Number (EISSN)

  • 1744-6880

Digital Object Identifier (DOI)

  • 10.1097/FPC.0b013e32835aa8a2

Language

  • eng

Conference Location

  • United States