Physicians' Academy for Cardiovascular Education

Monogenic FH associated with higher CVD risk compared with polygenic hypercholesterolemia

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

Literature - Trinder M, Francis GA, Brunham LR, - JAMA Cardiol. 2020. doi:10.1001/jamacardio.2019.5954

Introduction and methods

Familial hypercholesterolemia (FH) is an autosomal codominant genetic disorder caused by pathogenic variants in in LDLR, APOB, and PCSK9 genes that lead to an impairment in the removal of LDL from the blood [1-4]. The estimated prevalence of FH is 1 in 250 people and remains underdiagnosed and undertreated [5-7]. Patients with a monogenic FH-associated variant have a 2- to 3.5-fold increased risk of CVD compared to those with elevated LDL-c levels and no FH-associated variant [1,4]. 20% To 30% of patients with a phenotype of clinical FH have a polygenic cause [8,9]. It remains unknown whether polygenic hypercholesterolemia vs. hypercholesterolemia of unknown cause is associated with increased CVD risk. This study investigated whether the risk of atherosclerotic CVD differs between patients with monogenic hypercholesterolemia vs patients with polygenic hypercholesterolemia and how this risk compares with that of non-genetic hypercholesteremia.

This prospective cohort study used genotyping array and exome sequencing data from the UK Biobank cohort study [10-12] (478,428 individuals) to identify patients with monogenic hypercholesterolemia (n=277, pathogenic variants in LDLR, APOB, and PCSK9 genes), polygenic hypercholesterolemia (n=2379, LDL-c polygenic score higher than the 95th percentile based on 223 single-nucleotide variants [SNV]), or hypercholesterolemia with undetermined cause (n=2232). The weighted LDL-c polygenic scores were determined based on the effect sizes of 223 independent SNVs and calculated with the formula ∑ [βx* SNVx], where βx is the effect size of the cholesterol-increasing allele and SNVx is the number of LDL-c-increasing alleles (0,1, or 2) [13,14]. Risk for CVD events (coronary and carotid revascularization, myocardial infarction, ischemic stroke, and all-cause mortality) was compared between genetic and nongenetic etiology of hypercholesterolemia at comparable levels of LDL-c.

Main results


Among individuals with comparable levels of LDL-c, monogenic FH and polygenic hypercholesterolemia were associated with a higher CVD risk compared with hypercholesterolemia without an identifiable genetic cause. Monogenic FH was associated with the greatest CVD risk. These results suggest that knowledge of a possible genetic cause of hypercholesterolemia may provide prognostic information to better stratify CVD risk in patients. The finding that a large proportion of individuals with hypercholesterolemia were unaware of their LCL-c level and were not receiving cholesterol-lowering medication underlines the need for better recognition and management of hypercholesterolemia.


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Find this article online at JAMA Cardiol.

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