Polygenic risk scores improve coronary artery disease risk prediction alongside LDL

Polygenic risk scores (PRS), calculated based on genetic susceptibility variants, have been used to predict the risk of developing coronary artery disease (CAD). Medical student Colin Harper (Broad Institute of MIT and Harvard, MA, USA) presented an analysis evaluating how low-density lipoprotein cholesterol (LDL-C) concentrations can be combined with PRS to refine CAD risk prediction [1].

The study included 257,158 participants from the UK Biobank without prior CAD, stroke, diabetes, or lipid-lowering therapy at baseline, with a median follow-up of 13.5 years. Findings were replicated in 67,668 participants from the All of Us Research Program. In both cohorts, susceptibility to CAD was assessed using LDL-C levels and a CAD-specific PRS.

Overall, a higher PRS combined with lower LDL-C concentrations was associated with a CAD risk comparable to that conferred by severe hypercholesterolaemia (LDL-C ≥190 mg/dL) in both cohorts. CAD risk exceeded that associated with severe hypercholesterolaemia in individuals with PRS ≥2.6 and LDL-C 130–160 mg/dL, and PRS ≥2.8 with LDL-C 160–190 mg/dL. Furthermore, CAD risk was similar between severe hypercholesterolaemia and the following combinations: PRS ≥1.3 with LDL-C 160–190 mg/dL, PRS ≥1.4 with LDL-C 130–160 mg/dL, and PRS ≥1.9 with LDL-C 100–130 mg/dL.

Overall, the analysis showed that PRS can refine risk stratification beyond LDL-C levels alone, identifying individuals at high risk of CAD. “Participants with moderate LDL-C elevations and higher PRS may carry risk comparable to those with severe hypercholesterolaemia,” concluded medical student Colin Harper. “Incorporating PRS may identify high-risk individuals not captured by LDL-C thresholds alone.” However, the analysis did not assess therapy patterns; therefore, it remains unclear whether CAD risk is reduced with therapy to the same extent as in patients with severe hypercholesterolaemia.

Harper C, et al. Coronary artery disease polygenic risk scores refine low-density lipoprotein cholesterol-based risk stratification. ACC 2026, 28–30 March, New Orleans, LA, USA.