Abstract 14894: Performance of a Genome-Wide Polygenic Risk Score to Predict Coronary Events in Patients With Diabetes Without Prior Myocardial Infarction

Background:Patients with diabetes have an increased risk of MI. The prognostic value of a genome-wide polygenic risk score (GPS) developed in the general population for CAD compared with traditional cardiovascular and metabolic risk factors in diabetic patients is unknown.Methods:We studied 6,764 diabetic patients without prior MI from the SAVOR-TIMI 53 trial. The 6.6 million SNP GPS was calculated using the genotype dosage for each allele, multiplied by its weight, and then summed across all variants. Genetic risk categories were defined as low (Q1), intermediate (Q2-4), and high risk (Q5). The primary endpoint was a composite of MI or coronary heart death (CHD). Median follow up was 2 yrs. Cox proportional hazard regression analysis was performed adjusting for age, sex, and principle components 1-4 (ancestry). Similar analyses were done for traditional cardiovascular risk factors and all covariates were entered into a multivariable model to assess their independent strength.Results:There were 156 patients who had an MI or CHD during the trial. Compared with patients at low genetic risk, patients with high genetic risk were at a >2-fold (HR 2.15, 95% CI 1.25-3.71, p=0.006) and patients with intermediate risk were at a 68% higher risk (HR 1.68 [1.03-2.72], p=0.036) of MI or CHD. Of traditional clinical risk factors, GFR <60 mL/min/1.73m2and UACR >30 mg/g were the strongest predictors with approximately 2-fold increased risk of MI or CHD (HR 2.05, 95% CI 1.47-2.86, p<0.0001 & HR 1.98, 95% CI 1.44-2.74, p<0.0001, respectively). In a multivariable regression model (Figure), elevated genetic risk remained an independent predictor of a coronary event on par or above traditional risk factors.Conclusion:In patients with diabetes without prior myocardial infarction, a polygenic risk score is an independent predictor of MI that has prognostic value beyond established risk features, with patients in the top 20% of the risk score having a nearly 2.5-fold higher risk of MI or CHD.