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

Joshua P. Lewis, Richard B. Horenstein, Kathleen Ryan, Jeffrey R. O'Connell, Quince Gibson, Braxton D. Mitchell, Keith Tanner, Sumbul Chai, Kevin P. Bliden, Udaya S. Tantry, Cody J. Peer, William D. Figg, Shawn D. Spencer, Michael A. Pacanowski, Paul A. Gurbel, Alan R. Shuldiner

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalPharmacogenetics and Genomics
Volume23
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • CES1
  • carboxylesterase 1
  • clopidogrel
  • percutaneous coronary intervention
  • pharmacogenetics

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response'. Together they form a unique fingerprint.

Cite this