title: The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  Taken together, these findings suggest, for the first time, that genetic variation in CES1 may be an important determinant of the efficacy of clopidogrel.
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Lewis
authors.forename: Richard B
authors.initials: RB
authors.lastname: Horenstein
authors.forename: Kathleen
authors.initials: K
authors.lastname: Ryan
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: O'Connell
authors.forename: Quince
authors.initials: Q
authors.lastname: Gibson
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: Keith
authors.initials: K
authors.lastname: Tanner
authors.forename: Sumbul
authors.initials: S
authors.lastname: Chai
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Bliden
authors.forename: Udaya S
authors.initials: US
authors.lastname: Tantry
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Peer
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Spencer
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pacanowski
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gurbel
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
mesh_terms: D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010974:Platelet Aggregation / Q000187:drug effects* / Q000235:genetics; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; D004247:DNA; D000077144:Clopidogrel; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; D013988:Ticlopidine