Influence of Polygenic Background on the Clinical Presentation of Familial Hypercholesterolemia

Area of Science:

• Genetics
• Cardiology
• Public Health

Background:

• Familial hypercholesterolemia (FH) is a common genetic disorder affecting approximately 1 in 300 individuals globally.
• FH is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and a heightened risk of coronary artery disease (CAD).
• The wide spectrum of FH severity is not fully explained by established risk factors, suggesting underlying genetic influences.

Purpose of the Study:

• To investigate whether genome-wide genetic factors, quantified by polygenic risk scores (PRSs), contribute to the variable phenotypic severity observed in FH patients.
• To explore the association between PRSs for various cardiometabolic traits and the risk of atherosclerotic cardiovascular disease in individuals with FH.

Main Methods:

• Analysis of 1123 clinically diagnosed FH individuals from the FH Canada National Registry and 723 genetically identified FH individuals from the UK Biobank.
• Calculation of PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits using genome-wide gene array data.
• Comparison of PRS distributions between FH cohorts and non-FH controls, and examination of PRS association with atherosclerotic cardiovascular disease risk.

Main Results:

• Clinically diagnosed FH individuals exhibited higher LDL-C levels and a greater incidence of atherosclerotic cardiovascular disease compared to genetically identified FH individuals.
• Individuals with clinically diagnosed FH showed enrichment for higher PRSs related to CAD, LDL-C, and lipoprotein(a).
• A PRS for CAD was significantly associated with an increased risk of atherosclerotic cardiovascular disease among individuals carrying an FH-causing genetic variant.

Conclusions:

• Genome-wide genetic background, reflected in PRSs for CAD, LDL-C, and lipoprotein(a), plays a role in determining the phenotypic severity of FH.
• These findings enhance the understanding of factors contributing to FH's variable expressivity.
• A PRS for CAD could potentially improve cardiovascular disease risk prediction in individuals diagnosed with FH.