Influence of Polygenic Background on the Clinical Presentation of Familial Hypercholesterolemia.

Background: Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the FH population. This variability in expression is incompletely explained by known risk factors. We hypothesized that genome-wide genetic influences, as represented by polygenic risk scores (PRSs) for cardiometabolic traits, would influence the phenotypic severity of FH.

Methods: We studied individuals with clinically diagnosed FH (n=1123) from the FH Canada National Registry, as well as individuals with genetically identified FH from the UK Biobank (n=723). For all individuals, we used genome-wide gene array data to calculate PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits. We compared the distribution of PRSs in individuals with clinically diagnosed FH, genetically diagnosed FH, and non-FH controls and examined the association of the PRSs with the risk of atherosclerotic cardiovascular disease.

Results: Individuals with clinically diagnosed FH had higher levels of LDL-C, and the incidence of atherosclerotic cardiovascular disease was higher in individuals with clinically diagnosed compared with genetically identified FH. Individuals with clinically diagnosed FH displayed enrichment for higher PRSs for CAD, LDL-C, and lipoprotein(a) but not for other cardiometabolic risk factors. The CAD PRS was associated with a risk of atherosclerotic cardiovascular disease among individuals with an FH-causing genetic variant.

Conclusions: Genetic background, as expressed by genome-wide PRSs for CAD, LDL-C, and lipoprotein(a), influences the phenotypic severity of FH, expanding our understanding of the determinants that contribute to the variable expressivity of FH. A PRS for CAD may aid in risk prediction among individuals with FH.