Influence of Polygenic Background on the Clinical Presentation of Familial Hypercholesterolemia

Abstract

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.

Keywords: biological specimen banks; cardiovascular diseases; cholesterol, LDL; coronary artery disease; genetic risk score.

Figure 1.

Risk of atherosclerotic cardiovascular disease (ASCVD) events among individuals with monogenic familial hypercholesterolemia (FH) vs controls. ASCVD events were defined as myocardial infarction, coronary revascularization, or ischemic stroke. A, Crude time to an ASCVD is shown using age as the time scale. B, Odds ratios (ORs) for an ASCVD event with adjustment for age, sex, and the first 2 principal components of genetic ancestry are shown cases of monogenic FH vs controls. FHCAN: clinical FH indicates individuals from FH Canada with a clinical diagnosis of FH and without an FH-causing variant; FHCAN: FH, individuals from FH Canada with monogenic FH; FHCAN: non-FH, individuals from FH Canada without a clinical diagnosis of FH or FH-causing variant (unlikely or possible FH); UKB: clinical FH, individuals from the UK Biobank with LDL-C ≥5 mmol/L without an FH-causing variant; UKB: FH, individuals from UK Biobank with monogenic FH; and UKB: non-FH, individuals from UK Biobank with LDL-C <5 mmol/L without an FH-causing variant.

Figure 2.

Polygenic risk score (PRS) distribution. Violin plots with box plots are shown for PRS percentiles of coronary artery disease (CAD; A), LDL cholesterol (LDL-C; B), and lipoprotein(a; C) among individuals from FH Canada, the UKB, and the 1000 Genomes reference population (K1G). The box plots depict the median and interquartile range, while the whiskers depict the minimum and maximum values. PRS percentiles are calculated in reference to the appropriate 1000 Genomes Project superpopulation reference sample. FHCAN: clinical FH indicates individuals from FH Canada with a clinical diagnosis of FH and without an FH-causing variant; FHCAN: FH, individuals from FH Canada with monogenic FH; FHCAN: non-FH, individuals from FH Canada without a clinical diagnosis of FH or FH-causing variant (unlikely or possible FH); UKB: clinical FH, individuals from the UK Biobank with LDL-C ≥5 mmol/L without an FH-causing variant; UKB: FH, individuals from UK Biobank with monogenic FH; and UKB: non-FH, individuals from UK Biobank with LDL-C <5 mmol/L without an FH-causing variant.

Figure 3.

Polygenic risk scores (PRSs) of cardiometabolic risk factors among individuals with familial hypercholesterolemia (FH) and unaffected controls. The heat map displays the mean Z scores for atherosclerotic cardiovascular risk disease–related PRSs among individuals from FH Canada, the UKB, and the 1000 Genomes reference population (K1G). The distribution of PRSs was determined relative to the 1000 Genomes reference population (normal distribution with a mean of 0 and SD of 1). CAD indicates coronary artery disease; FHCAN: clinical FH, individuals from FH Canada with a clinical diagnosis of FH and without an FH-causing variant; FHCAN: FH, individuals from FH Canada with monogenic FH; FHCAN: non-FH, individuals from FH Canada without a clinical diagnosis of FH or FH-causing variant (unlikely or possible FH); HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SLE, systemic lupus erythematosus; UKB: clinical FH, individuals from the UK Biobank with LDL-C ≥5 mmol/L without an FH-causing variant; UKB: FH, individuals from UK Biobank with monogenic FH; and UKB: non-FH, individuals from UK Biobank with LDL-C <5 mmol/L without an FH-causing variant.

Figure 4.

Effect of polygenic risk scores on the risk of atherosclerotic cardiovascular disease (ASCVD) among individuals with monogenic familial hypercholesterolemia (FH). Fixed-effects meta-analyses are displayed for the association and polygenic risk scores for (A) coronary artery disease, (B) low-density lipoprotein cholesterol, and (C) lipoprotein(a) with the risk of ASCVD. The risk of ASCVD associated with an increase in 1-SD unit of polygenic risk score is displayed. Analyses were adjusted for age, sex, and the first 2 principal components of genetic ancestry. FHCAN indicates individual with monogenic FH from the FH Canada cohort; OR, odds ratio; and UKB, individuals with monogenic FH from the UK Biobank cohort.