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Published on: September 15, 2018
Influence of Polygenic Background on the Clinical Presentation of Familial Hypercholesterolemia
Mark Trinder1, Lubomira Cermakova1, Isabelle Ruel2
1Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, Vancouver, Canada (M.T., L.C., L.R.B.).
Insights
Polygenic risk scores (PRSs) for coronary artery disease (CAD) and LDL-C influence the severity of familial hypercholesterolemia (FH). These genetic factors may help predict cardiovascular disease risk in FH patients.
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.
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.
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