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Original Investigation
February 12, 2020

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

Author Affiliations
  • 1Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada
  • 2Experimental Medicine Program, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  • 3Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  • 4Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
JAMA Cardiol. Published online February 12, 2020. doi:10.1001/jamacardio.2019.5954
Key Points

Question  Does the risk of atherosclerotic cardiovascular disease (CVD) differ between individuals with monogenic hypercholesterolemia vs those with polygenic hypercholesterolemia?

Findings  In this cohort study of 48 741 adults recruited by the UK Biobank, a monogenic cause for hypercholesterolemia was found in 277 participants (0.57%) and a polygenic cause in 2379 participants (4.9%). Both polygenic and monogenic causes of hypercholesterolemia appeared to be associated with an increased risk of CVD compared with hypercholesterolemia with an unknown genetic cause; however, monogenic hypercholesterolemia was associated with the greatest risk of CVD.

Meaning  The findings of this study suggest that among individuals with comparable levels of low-density lipoprotein cholesterol, monogenic hypercholesterolemia may be associated with the greatest risk of CVD followed by polygenic hypercholesterolemia.

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.

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