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

Published

Journal Article

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.

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

International Standard Serial Number (ISSN)

  • 1744-6872

Digital Object Identifier (DOI)

  • 10.1097/FPC.0b013e32835aa8a2

Language

  • eng