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

Pharmacogenet Genomics. 2013 Jan;23(1):1-8. doi: 10.1097/FPC.0b013e32835aa8a2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Carboxylic Ester Hydrolases / genetics*
  • Clopidogrel
  • Coronary Artery Disease / drug therapy
  • Coronary Artery Disease / enzymology
  • Coronary Artery Disease / genetics*
  • DNA / genetics
  • Female
  • Genotype
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Pharmacogenetics*
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation / genetics
  • Platelet Aggregation Inhibitors / metabolism*
  • Platelet Aggregation Inhibitors / therapeutic use
  • Polymerase Chain Reaction
  • Polymorphism, Genetic / genetics*
  • Prognosis
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / metabolism
  • Ticlopidine / therapeutic use


  • Platelet Aggregation Inhibitors
  • DNA
  • Clopidogrel
  • Carboxylic Ester Hydrolases
  • CES1 protein, human
  • Ticlopidine