Precision Risk Stratification and Genetic Profiling

Genetic risk based on polygenic scores (PGS) for low-density lipoprotein cholesterol (LDL-C) can identify individuals who may benefit from more intensive monitoring and therapeutic management, according to an analysis by Dr So Mi Jemma Cho (Massachusetts General Hospital, MA, USA) [1].

The study used data from patients included in the Massachusetts General Hospital Brigham Biobank, with and without atherosclerotic cardiovascular disease. Data were analysed for 2,065 patients in the primary prevention cohort (index date: initiation of first lipid-lowering medication) and 1,331 patients in the secondary prevention cohort (index date: first atherosclerotic cardiovascular disease event). Both cohorts had index events between 2014 (following the 2013 ACC/AHA cholesterol guidelines) and 2021, with a 3-year follow-up to assess longitudinal LDL-C control. Analyses were adjusted for demographic characteristics (age, sex, race and ethnicity, body mass index) and clinical variables (smoking status, lipid levels, blood pressure, eGFR, diabetes, antihypertensive use, and use of antihypertensive and lipid-lowering medications).

Mean (standard deviation [SD]) LDL-C at baseline was 127.1 (42.1) mg/dL in the primary prevention cohort, and 113.0 (36.0) mg/dL in the secondary prevention cohort. Association analyses were conducted between the cumulative fraction of LDL-C above guideline-recommended targets (based on ACC/AHA guidelines) and PGS. For each SD increase in PGS, patients in the primary prevention cohort had a 4.26 mg/dL (95% CI 3.12–5.40) higher cumulative LDL-C above target, while those in the secondary prevention cohort had a 5.00 mg/dL (95% CI 3.37–6.63) higher cumulative LDL-C above target. Overall, LDL-C PGS was independently associated with long-term LDL-C control in both prevention cohorts, irrespective of demographic, lifestyle, and clinical risks, or medication use.

In summary, LDL-C PGS identified individuals with earlier and higher increases in LDL-C who may not achieve optimal management. “Awareness of elevated genetic risk for LDL-C may improve identification of individuals requiring intensive management and those who may benefit from novel lipid-lowering strategies,” concluded Dr Cho.

Cho SMJ, et al. Low-density lipoprotein cholesterol polygenic score predicts cumulative cholesterol burden above target. ACC 2026, 28–30 March, New Orleans, LA, USA.

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.

Polygenic scores can identify individuals at risk of an increase in LDL-C over time

Polygenic risk scores improve coronary artery disease risk prediction alongside LDL