Association of Monogenic vs Polygenic Hypercholesterolemia With Risk of Atherosclerotic Cardiovascular Disease

Abstract

Importance: Monogenic familial hypercholesterolemia (FH) is associated with lifelong elevations in low-density lipoprotein cholesterol (LDL-C) levels and increased risk of atherosclerotic cardiovascular disease (CVD). However, many individuals with hypercholesterolemia have a polygenic rather than a monogenic cause for their condition. It is unclear if a genetic variant for hypercholesterolemia alters the risk of CVD.

Objectives: To assess whether a genetic variant for hypercholesterolemia alters the risk of atherosclerotic CVD and to evaluate how this risk compares with that of nongenetic hypercholesterolemia.

Design, setting, and participants: In this genetic-association, case-control, cohort study, individuals aged 40 to 69 years were recruited by the UK Biobank from across the United Kingdom between March 13, 2006, and October 1, 2010, and followed up until March 31, 2017. Genotyping array and exome sequencing data from the UK Biobank cohort were used to identify individuals with monogenic (LDLR, APOB, and PCSK9) or polygenic hypercholesterolemia (LDL-C polygenic score >95th percentile based on 223 single-nucleotide variants in the entire cohort). The data were analyzed from July 1, 2019, to December 30, 2019.

Main outcomes and measures: The study investigated the association of genotype with the risk of coronary and carotid revascularization, myocardial infarction, ischemic stroke, and all-cause mortality among the overall study population and among participants with monogenic FH (n = 277), polygenic hypercholesterolemia (n = 2379), or hypercholesterolemia with undetermined cause (n = 2232) at comparable levels of LDL-C measured at study enrollment.

Results: For the 48 741 individuals with genotyping array and exome sequencing data, the mean (SD) age was 56.6 (8.0) years, and 54.5% were female (n = 26 541 of 48 741). A monogenic FH variant for hypercholesterolemia was found in 277 individuals (0.57%, 1 in 176 individuals). Participants with monogenic FH were significantly more likely than those without monogenic FH to experience an atherosclerotic CVD event at 55 years or younger (17 of 277 [6.1%] vs 988 of 48 464 [2.0%]; P < .001). Compared with the general population, both monogenic and polygenic hypercholesterolemia were associated with an increased risk of CVD events. Moreover, among individuals with comparable levels of LDL-C, both monogenic (hazard ratio, 1.93; 95% CI, 1.34-2.77; P < .001) and polygenic hypercholesterolemia (hazard ratio, 1.26; 95% CI, 1.03-1.55; P = .03) were significantly associated with an increased risk of CVD events compared with the risk of such events in individuals with hypercholesterolemia without an identified genetic cause.

Conclusions and relevance: The findings of this study suggest that among individuals with hypercholesterolemia, genetic determinants of LDL-C levels may impose additional risk of CVD. Thus, understanding the possible genetic cause of hypercholesterolemia may provide important prognostic information to treat patients.

Figure 1.. Flow Diagram of UK Biobank Cohort Subgroups Used in the Study

LDL-C indicates low-density lipoprotein cholesterol; SNV, single-nucleotide variant.

Figure 2.. Low-Density Lipoprotein Cholesterol (LDL-C) Polygenic Scores and LDL-C Levels and Risk of Cardiovascular Disease (CVD) Among all Individuals in the Genotyping Array Cohort

A, The distribution of LDL-C polygenic scores is depicted for the African, East Asian, and European ancestral superpopulations. B, The linear association between LDL-C polygenic scores and LDL-C levels (to convert to millimoles per liter, multiply by 0.0259) are depicted. Lines depict linear regression analyses segregated by ancestral superpopulation. C, The adjusted hazard ratios (aHRs) with 95% CIs for composite CVD events of myocardial infarction, coronary or carotid revascularization, ischemic stroke, or all-cause mortality are depicted for each decile of LDL-C polygenic score percentile (percentiles are calculated relative to each individual’s ancestral superpopulation). Hazard ratios were adjusted for age, sex, genotyping array and/or batch, and the first 4 principal components of ancestry.

Figure 3.. Monogenic Familial Hypercholesterolemia (FH)-Associated Variants and Elevated Low-Density Lipoprotein Cholesterol (LDL-C) Level

A, Density plot shows the distribution of LDL-C levels (to convert to millimoles per liter, multiply by 0.0259) at enrollment between individuals with an FH-associated variant (mono+) and those without an FH-associated variant (mono−). B, The LDL-C levels are depicted for individuals with an FH-associated variant classified as likely pathogenic or pathogenic in ClinVar, an FH-associated variant predicted to be pathogenic, and individuals with no detected FH-associated variants. The box plots depict the median and interquartile range, with the vertical black lines displaying the minimum to maximum. ^aP < .0001.

Figure 4.. Monogenic Familial Hypercholesterolemia (FH) vs Polygenic Hypercholesterolemia and Cardiovascular Disease (CVD) Events

A, Boxplots display the median, interquartile range, and minimum to maximum of direct low-density lipoprotein cholesterol (LDL-C) levels (to convert to millimoles per liter, multiply by 0.0259) that are adjusted for cholesterol-lowering medication among individuals with monogenic FH (mono+), polygenic hypercholesterolemia (poly+; 223 single-nucleotide variants LDL-C polygenic score >95th percentile), and individuals with hypercholesterolemia of no known genetic cause (LDL+). B, Time-to-first-event analyses are depicted for composite CVD events, including myocardial infarction, coronary or carotid revascularization, ischemic stroke, or all-cause mortality. Individuals were stratified based on the rank order groupings of nongenetic hypercholesterolemia, polygenic hypercholesterolemia, or monogenic FH. C, Hazard ratios (HRs) with 95% CIs are displayed for composite CVD events with or without adjustment for LDL-C levels. All HRs were adjusted for age, sex, genotyping array or batch, and the first 4 principal components of ancestry.