Polygenic risk scores enhance LDL cholesterol–based risk stratification for coronary artery disease

Genetic risk for coronary artery disease (CAD) can be estimated using polygenic risk scores (PRS), but greater clarity is needed on how PRS might inform clinical risk assessment and prevention. We assessed the risk for CAD jointly conferred by LDL-C and CAD PRS relative to established treatment thresholds. This study followed 257,158 UK Biobank (UKBB) participants and 67,668 from the All of Us Research Program (AoU), a longitudinal U.S. cohort, without prior CAD, stroke, or diabetes. In UKBB, Cox proportional hazards models estimated CAD hazard ratios for each LDL-C × CAD PRS stratum relative to individuals with LDL-C <100 mg/dL. The severe hypercholesterolemia (LDL-C ≥190 mg/dL) group, the guideline-designated threshold for statin initiation, served as a benchmark against which groups were compared. Parallel analyses were performed in AoU cross-sectionally. Over a median (IQR) follow-up of 13.5 (12.8–14.2) years, 13,886 (5.4%) participants developed CAD in UKBB. Higher CAD PRS was associated with CAD risk that was comparable to, or in some strata exceeding, that associated with LDL-C ≥190 mg/dL by pairwise Wald tests at progressively lower LDL-C concentrations in both cohorts. Individuals with high genetic risk and moderate LDL-C elevations, representing 14.8% of the study population, have CAD risk comparable to or greater than that of SH. Consideration of dynamic LDL-C thresholds among those with high CAD PRS may identify individuals with risk sufficiently high to warrant preventive therapy.