title: Impact of genetic variants on post-clopidogrel platelet reactivity in patients after elective percutaneous coronary intervention.
abstract: OBJECTIVE
  To determine the effect of various SNPs on post-clopidogrel platelet reactivity and clinical outcome.
  
  
  METHODS
  Cytochrome 2C19 (CYP2C19) loss-of-function (LOF; *2, *3) and gain-of-function (GOF; *17) allelic variants, together with ABCB1 (3435 C→T and 2677 G→T/A) and paraoxonase-1 (PON-1; 192 Q→R) SNPs were analyzed in 189 patients after elective stent implantation who participated in a randomized, placebo-controlled trial (NCT00638326). Platelet reactivity was determined with light transmission aggregometry and vasodilator stimulated phosphoprotein phosphorylation (VASP-PRI) 12-24 h after 600 mg clopidogrel. High on-treatment platelet reactivity (HTPR) was defined according to the consensus definition (ADP 5 µM >46%; VASP-PRI>50%).
  
  
  RESULTS
  In the case of CYP2C19 genotypes, a gene-dose effect was observed in ADP reactivity with the lowest values in GOF homozygotes and the highest degree in patients carrying two LOF alleles. The odds for HTPR also increased with the number of LOF alleles. There were no significant differences in platelet reactivity according to PON-1 or ABCB1 genotypes. In multivariate analysis, the presence of a CYP2C19 LOF allele turned out to be the independent determinant of HTPR. Although the study was not powered to clinical outcome (not LOF heterozygotes), only patients with two LOF alleles had a significantly higher risk for cardiovascular death, myocardial infarction or unplanned target vessel revascularization at 1 year compared with non-LOF carriers.
  
  
  CONCLUSIONS
  Genetic variants in CYP2C19 have a gene-dose effect on post-clopidogrel platelet reactivity, with homozygote LOF carriers having the highest risk for HTPR and for adverse ischemic events. Neither ABCB1 nor PON-1 genotypes significantly influenced platelet reactivity or outcome.
authors.affiliation: Institute of Laboratory Medicine, University of Pécs, 13 Ifjúság Street, H-7624 Pecs, Hungary.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Rideg
authors.forename: András
authors.initials: A
authors.lastname: Komócsi
authors.forename: Tamás
authors.initials: T
authors.lastname: Magyarlaki
authors.forename: Margit
authors.initials: M
authors.lastname: Tokés-Füzesi
authors.forename: Attila
authors.initials: A
authors.lastname: Miseta
authors.forename: Gábor L
authors.initials: GL
authors.lastname: Kovács
authors.forename: Dániel
authors.initials: D
authors.lastname: Aradi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000368:Aged; D000483:Alleles; D015906:Angioplasty, Balloon, Coronary; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D043303:Aryldialkylphosphatase / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000494:pharmacology; D000077144:Clopidogrel; D023921:Coronary Stenosis / Q000601:surgery*; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000494:pharmacology; D008875:Middle Aged; D010750:Phosphoproteins / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D020641:Polymorphism, Single Nucleotide; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016896:Treatment Outcome; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D000098662:Vasodilator-Stimulated Phosphoprotein; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D043303:Aryldialkylphosphatase; D013988:Ticlopidine