LDL-C AND POLYGENIC RISK FOR CORONARY HEART DISEASE RISK ASSESSMENT

Therapeutic Area

ASCVD/CVD Risk Assessment

Background

Elevated concentrations of LDL-cholesterol (LDL-C) are a major independent modifiable risk factor for coronary heart disease (CHD). However, the joint consideration of LDL-C and background polygenic risk in assessing risk remains unclear.

Methods

We utilized data from a subset of the Genetic Epidemiology Resource in Adult Health and Aging (GERA) Multi-Ethnic cohort (n=47,576) who were without diabetes and not taking cholesterol lowering medication at baseline in 2007-2008. We stratified the cohort into three groups of CHD genetic risk (low=quintile 1; intermediate=quintiles 2, 3 and 4; and high=quintile 5) using a 12-SNP Polygenic Risk Score (PRS) for CHD (CARDIO inCode-Score, GENinCode Plc). Incident CHD consisted of primary in-patient codes for angina pectoris, myocardial infarction, revascularization procedures or CHD death through 12/31/2022 (n=1,678); mean follow-up was 13.8 years. Age-adjusted CHD rates per 10,000 person-years were estimated using Poisson regression (accounting for death and health plan disenrollment) according to polygenic risk and LDL-C level. Hazard ratios and 95% confidence intervals for 1 standard deviation (SD) increment of LDL-C in each PRS group were obtain using Cox regression adjusting for 10 principal components of ancestry plus traditional risk factors. We tested for formal interaction LDL-C*PRS as continuous variables in the fully adjusted model.

Results

Mean ± SD age = 58.1 ± 10.3 years; 62% female; 18% non-European ancestry. There were nonstatistically significant associations between LDL-C and incident CHD among low polygenic risk individuals, although individuals with severe hypercholesterolemia (≥190 mg/dL) in this group had a markedly elevated HR (2.3; p=0.06) (Table and forest plot). In the intermediate polygenic risk group, there was a steady increased risk of CHD as LDL-C increased, with markedly higher HR (>2.0) starting at 160 mg/dL. In the high polygenic risk group, HR of CHD began to increase markedly starting at LDL-C of 130 mg/dL, and the combination of both high polygenic risk and severe hypercholesterolemia (LDL-C > 190 mg/dL) was associated with a HR of 3.6.

Conclusions

These results have important clinical implications for lipid management in asymptomatic populations and support a more aggressive management and primary prevention for individuals with high polygenic risk.