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

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.