Impact of Insulin Receptor Suostrate-1 rs956115 and CYP2C19 rs4244285 Genotypes on Clinical Outcome of Patients Uncergoing Percutaneous Coronary Intervention

BACKGROUND: Insulin receptor substrate-1 (IRS-1) rs956115 is associated with vascular risk in patients with coronary artery disease and concomitant diabetes. CYP2C19*2 (rs4244285) modulates clopidogrel response and predicts the outcome of coronary artery disease. This study was designed to explore the association between IRS-1, CYP2C19*2 genotypes, platelet reactivity, and 1-year outcome in patients with coronary artery disease undergoing percutaneous coronary intervention. METHODS AND RESULTS: Genotyping was performed using an improved multiplex ligation detection reaction technique. Platelet aggregation was assessed by light transmission aggregometry. Major adverse cardiovascular events were defined as a composite of cardiovascular death, myocardial infarction, and ischemic stroke. A total of 2213 consecutive patients were screened and 1614 were recruited. At 1 month, patients with IRS-1 CG genotype had significantly lower levels of ADP-induced platelet aggregation compared with patients with CC homozygotes. Patients with IRS-1 CG or GG genotype had a 2.09-fold higher risk of major adverse cardiovascular events compared with those with CC homozygotes (95% CI, 1.04-4.19; P=0.0376). By comparison, patients with CYP2C19*2 GA or AA genotype had higher ADP-induced platelet aggregation compared with patients with GG homozygotes. Although there was no significant difference in risk of major adverse cardiovascular events between patients with GA/AA and GG genotypes, patients with GA genotype had a 2.19-fold higher risk than those with GG homozygotes (95% CI, 1.13-4.24; P=0.0200). No interaction between IRS-1 and CYP2C19*2 genotypes was observed. CONCLUSIONS: In patients following percutaneous coronary intervention, IRS-1 GG/CG and CYP2C19*2 GA genotypes were associated with 2.09- and 2.19-fold increased cardiovascular risk, respectively, at 1-year follow-up. The association between IRS-1 genotypes and major adverse cardiovascular events appeared to be independent of known clinical predictors.