BackgroundGenetic risk scores (GRS) composed of single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD) have been shown to predict cardiovascular risk in primary and secondary prevention populations. We tested whether an expanded CAD-GRS predicted risk of recurrent coronary events in patients presenting with acute coronary syndrome (ACS).MethodsWe genotyped 6,404 individuals from the genetics substudy of the IMPROVE-IT trial, which tested whether the addition of ezetimibe to statin therapy improves cardiovascular outcomes. We studied the association of an updated CAD-GRS that included 75 genetic variants, with a composite outcome of coronary heart disease death, myocardial infarction or urgent coronary revascularization, adjusting, importantly, for the clinical TIMI Risk Score for Secondary Prevention.ResultsWhen divided into low (quintile 1), intermediate (quintiles 2-4) and high (quintile 5) genetic risk categories, a significant gradient in risk for recurrent cardiovascular events was observed such that, after adjusting for clinical risk factors, patients in the highest genetic risk category had a 44% greater risk compared to those in the lowest genetic risk category (P=0.0004) Figure. In terms of the benefit of ezetimibe vs. placebo, the hazard ratios and absolute risk reductions were 0.89 (95% CI 0.65-1.21) & 2.0%, 0.94 (95% CI 0.80-1.11) & 0.6% and 0.82 (95% CI 0.63-1.07) & 3.1% for the low, intermediate and high genetic risk categories, respectively.ConclusionAn expanded GRS composed of 75 CAD-associated SNPs identifies patients presenting with ACS who are at significantly increased risk of recurrent coronary events independent of clinical risk factors. Patients with the highest burden of genetic risk tended to derive the largest relative and absolute clinical benefit from ezetimibe therapy.