Abstract 14750: Performance of a Polygenic Risk Score for Coronary Artery Disease Across the Spectrum of ASCVD: An Analysis of 60k Patients From 6 TIMI Randomized Trials

Abstract

Background: Coronary artery disease (CAD) polygenic risk scores (PRS) may improve risk stratification, but whether performance differs by ASCVD status remains unclear. Purpose: To compare the predictive ability of a CAD PRS for coronary events in pts with ASCVD and prior event, ASCVD without event, and without overt ASCVD. Methods: We studied genotyped pts from 6 multinational TIMI RCTs. Using a 2.3 million SNP CAD PRS, we first assigned pts to low (Q1), intermediate (Q2-4), or high (Q5) genetic risk, after which pts were grouped by ASCVD status at baseline. The primary endpoint was any coronary event, a composite of death from coronary disease, myocardial infarction, or coronary revascularization. Cox proportional hazards models were used to estimate risk of events, adjusted for ancestry (principal components 1-5), age, sex, SBP, eGFR, diabetes, smoking, and trial. Results: We included 59,905 pts (mean age 66 yrs; 71% male; 79% with prior ASCVD; 49% with diabetes), of whom 10.6% had coronary events during follow-up. Compared with low genetic risk pts, event rates were greater in intermediate (HR 1.59 [95% CI 1.47-1.71]; p<0.001) and high (HR 2.08 [1.91-2.27]; p<0.001) genetic risk pts. There was a significant interaction between the CAD PRS and clinical ASCVD (P interaction <0.001), such that genetic risk discriminated relative risk of future coronary events more strongly in pts without overt ASCVD ( Fig 1A ). In this subgroup, high genetic risk pts had a nearly 5-fold higher hazard of events than low genetic risk pts (8.5% vs 1.6% at 3 yrs; HR 4.63 [3.46-6.21]; p<0.001). Pts without clinical ASCVD and high genetic risk had event rates comparable to pts with established ASCVD and low genetic risk ( Fig 1B ). Conclusion: The gradient of relative risk prediction of coronary events from a CAD PRS depends on the presence of known ASCVD and is strongest in patients without clinical disease. Genetic risk stratification may be more useful in pts without overt ASCVD to help focus preventive measures.