title: Genetic determinants of on-aspirin platelet reactivity: focus on the influence of PEAR1.
abstract: BACKGROUND
  Platelet aggregation during aspirin treatment displays considerable inter-individual variability. A genetic etiology likely exists, but it remains unclear to what extent genetic polymorphisms determine platelet aggregation in aspirin-treated individuals.
  
  
  OBJECTIVE
  To identify platelet-related single nucleotide polymorphisms (SNPs) influencing platelet aggregation during aspirin treatment. Furthermore, we explored to what extent changes in cyclooxygenase-1 activity and platelet activation may explain such influence.
  
  
  METHODS
  We included 985 Danish patients with stable coronary artery disease treated with aspirin 75 mg/day mono antiplatelet therapy. Patients were genotyped for 16 common SNPs in platelet-related genes using standard PCR-based methods (TaqMan). Platelet aggregation was evaluated by whole blood platelet aggregometry employing Multiplate Analyzer (agonists: arachidonic acid and collagen) and VerifyNow Aspirin. Serum thromboxane B2 was measured to confirm aspirin adherence and was used as a marker of cyclooxygenase-1 activity. Soluble P-selectin was used as marker of platelet activation. Platelet aggregation, cyclooxygenase-1 activity, and platelet activation were compared across genotypes in adjusted analyses.
  
  
  RESULTS
  The A-allele of the rs12041331 SNP in the platelet endothelial aggregation receptor-1 (PEAR1) gene was associated with reduced platelet aggregation and increased platelet activation, but not with cyclooxygenase-1 activity. Platelet aggregation was unaffected by the other SNPs analyzed.
  
  
  CONCLUSIONS
  A common genetic variant in PEAR1 (rs12041331) reproducibly influenced platelet aggregation in aspirin-treated patients with coronary artery disease. The exact biological mechanism remains elusive, but the effect of this polymorphism may be related to changes in platelet activation. Furthermore, 14 SNPs previously suggested to influence aspirin efficacy were not associated with on-aspirin platelet aggregation.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01383304.
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; Department of Internal Medicine, Regional Hospital West Jutland, Herning, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Würtz
authors.affiliation: Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Nissen
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Erik Lerkevang
authors.initials: EL
authors.lastname: Grove
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Steen Dalby
authors.initials: SD
authors.lastname: Kristensen
authors.affiliation: Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Anne-Mette
authors.initials: AM
authors.lastname: Hvas
mesh_terms: D000368:Aged; D001241:Aspirin / Q000494:pharmacology*; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000235:genetics; D051545:Cyclooxygenase 1 / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*
chemical_list: C502809:PEAR1 protein, human; D011956:Receptors, Cell Surface; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D001241:Aspirin