title: Impact of insulin receptor substrate-1 genotypes on platelet reactivity and cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease.
abstract: OBJECTIVE
  The aim of this study was to assess the association between genetic variants of the insulin receptor substrate (IRS)-1 gene, platelet function, and long-term outcomes in patients with type 2 diabetes mellitus (DM) and stable coronary artery disease while on aspirin and clopidogrel therapy.
  
  
  BACKGROUND
  The effects of pharmacogenetic determinants on platelet function and cardiovascular outcomes in type DM patients are unknown.
  
  
  METHODS
  The association between IRS-1 genetic variants, platelet function, and the risk of major adverse cardiac events (MACE) at 2 years was assessed in 187 patients with type 2 DM and stable coronary artery disease on maintenance aspirin and clopidogrel therapy.
  
  
  RESULTS
  Seven tag single nucleotide polymorphisms were selected. Individuals with high platelet reactivity were more frequent among carriers of the C allele (GC and CC genotypes; approximately 20% of population) of the rs956115 marker (44.4% vs. 20.5%; odds ratio: 3.1, 95% confidence interval [CI]: 1.44 to 6.67; p = 0.006). These patients were at higher risk of MACE (28.0% vs. 10.9%; hazard ratio: 2.90, 95% CI: 1.38 to 6.11; p = 0.005). The C allele carriers of the rs956115 marker were more commonly associated with a hyperreactive platelet phenotype. This was confirmed in an external validation cohort of patients with type 2 DM but not in an external validation cohort of patients without DM. Carriers of the C allele of the rs956115 marker also had a significantly higher risk of MACE compared with noncarriers (30.6% vs. 11.4%; hazard ratio: 2.88, 95% CI: 1.35 to 6.14; p = 0.006).
  
  
  CONCLUSIONS
  Type 2 DM patients who are carriers of the C allele of the rs956115 marker of the IRS-1 gene have a hyperreactive platelet phenotype and increased risk of MACE.
authors.affiliation: Division of Cardiology, College ofMedicine, University of Florida-Jacksonville, 655 West 8th Street, Jacksonville, FL 32209, USA. dominick.angiolillo@jax.ufl.edu
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
authors.forename: Esther
authors.initials: E
authors.lastname: Bernardo
authors.forename: Martina
authors.initials: M
authors.lastname: Zanoni
authors.forename: David
authors.initials: D
authors.lastname: Vivas
authors.forename: Piera
authors.initials: P
authors.lastname: Capranzano
authors.forename: Giovanni
authors.initials: G
authors.lastname: Malerba
authors.forename: Davide
authors.initials: D
authors.lastname: Capodanno
authors.forename: Paola
authors.initials: P
authors.lastname: Prandini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pasquali
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Trabetti
authors.forename: Manel
authors.initials: M
authors.lastname: Sabaté
authors.forename: Pilar
authors.initials: P
authors.lastname: Jimenez-Quevedo
authors.forename: Jose L
authors.initials: JL
authors.lastname: Ferreiro
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ueno
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Bass
authors.forename: Pier Franco
authors.initials: PF
authors.lastname: Pignatti
authors.forename: Antonio
authors.initials: A
authors.lastname: Fernandez-Ortiz
authors.forename: Carlos
authors.initials: C
authors.lastname: Macaya
mesh_terms: D000483:Alleles; D001792:Blood Platelets; D002318:Cardiovascular Diseases / Q000235:genetics*; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000150:complications* / Q000235:genetics*; D048909:Diabetes Complications / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics*; D008297:Male; D016017:Odds Ratio; D010641:Phenotype; D012306:Risk; D016896:Treatment Outcome
chemical_list: D005819:Genetic Markers; D055504:Insulin Receptor Substrate Proteins