Polygenic risk score predicts prevalence of cardiovascular disease in patients with familial hypercholesterolemia

Abstract

Background Although familial hypercholesterolemia (FH) is a severe monogenic disease, it has been shown that clinical risk factors and common genetic variants can modify cardiovascular disease (CVD) risk. Objective The aim of the study was to evaluate the polygenic contribution to lipid traits and CVD in FH using genetic risk scores (GRSs). Methods Among the 20,434 subjects attending the lipid clinic, we identified and included 725 individuals who carried an FH causing mutation in this retrospective cohort study. We evaluated the association of GRSs for several traits including coronary artery disease (CAD; GRS CAD ) as well as plasma concentrations of low-density lipoprotein cholesterol (LDL-C; GRS LDL-C ), high-density lipoprotein cholesterol (GRS HDL-C ) and triglycerides (GRS TG ). Results A total of 32% (n = 231) of FH subjects presented a CVD event before their first visit. Patients in the highest GRS LDL-C tertile presented an LDL-C 0.4 mmol/L (15.5 mg/dL) higher than the subjects in the lowest tertile (P = .01). The GRS CAD was strongly associated with CVD events (odds ratio 1.80; 95% confidence interval 1.14-2.85; P = .01) even after adjustment for cardiovascular risk factors. Compared with subjects in the first tertile, those in the third GRS CAD tertile had a significantly higher prevalence of events (40.9% vs 24.7%, P Conclusion These results indicate that even in the context of a severe monogenic disease such as FH, common genetic variants can significantly modif…