title: Paraoxonase-1 Q192R polymorphism and antiplatelet effects of clopidogrel in patients undergoing elective coronary stent placement.
abstract: BACKGROUND
  Recently published data indicate that the paraoxonase-1 (PON1) Q192R genotype-and not as previously shown activity of cytochrome P450 (CYP) 2C19-is the major determinant of metabolic bioactivation of clopidogrel and thereby variability of antiplatelet effect of clopidogrel. We sought to investigate whether the PON1 Q192R gene polymorphism affects platelet reactivity in patients undergoing elective coronary stent placement.
  
  
  RESULTS
  The study included 760 consecutive patients undergoing elective coronary stent placement after loading with clopidogrel 600 mg. Platelet function was assessed by adenosine diphosphate-induced (ADP 5 and 20 μmol/L) platelet aggregation and by flow-cytometric analysis of platelet surface protein expression before clopidogrel, at the time of coronary stent placement, and before discharge after coronary stent placement. PON1 Q192R genotype [NM_000446.5:c.575A>G single nucleotide polymorphism (rs662)] was analyzed by TaqMan polymerase chain reaction. Residual platelet aggregation (ADP 5 μmol/L) at predischarge was 8.0% (3.0% to 17.0%) [median (interquartile range)] in PON1 QQ192 patients (n=384), 8.0% (3.0% to 15.0%) in PON1 QR192 (n=304), and 11.0% (3.0% to 18.0%) in PON1 RR192 (n=72; P=0.603). By multivariable linear regression, residual platelet aggregation was not associated with PON1 QQ192/QR192 (partial η(2)<0.001, P=0.728) but with CYP2C19*2 loss-of-function allele (partial η(2)=0.045, P<0.001) as well as any CYP2C19*17 gain-of-function allele (partial η(2)=0.012, P=0.004). All other platelet assays also showed no significant association between PON1 Q192R genotype and antiplatelet effect of clopidogrel. The 1-year incidence of death and myocardial infarction did not differ between PON1 Q192R genotypes.
  
  
  CONCLUSIONS
  On-treatment platelet reactivity in patients undergoing coronary stent placement after loading with clopidogrel 600 mg was not associated with PON1 Q192R genotype.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00457236.
authors.affiliation: Herz-Zentrum Bad Krozingen, Germany. dietmar.trenk@herzzentrum.de
authors.forename: Dietmar
authors.initials: D
authors.lastname: Trenk
authors.forename: Willibald
authors.initials: W
authors.lastname: Hochholzer
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
authors.forename: Oliver
authors.initials: O
authors.lastname: Zolk
authors.forename: Christian M
authors.initials: CM
authors.lastname: Valina
authors.forename: Christian
authors.initials: C
authors.lastname: Stratz
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Neumann
mesh_terms: D043303:Aryldialkylphosphatase / Q000235:genetics*; D000077144:Clopidogrel; D017558:Elective Surgical Procedures; D005838:Genotype; D006801:Humans; D020125:Mutation, Missense; D010974:Platelet Aggregation / Q000187:drug effects* / Q000235:genetics*; D010975:Platelet Aggregation Inhibitors; D010979:Platelet Function Tests; D020641:Polymorphism, Single Nucleotide; D015607:Stents; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D043303:Aryldialkylphosphatase; D013988:Ticlopidine