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

  • A correlation between LDL-c levels and LDL-c polygenic scores was observed in the overall cohort (n=455,191, multiple R²= 0.09; β [SE] = 27.78 [0.18]; P<0.001).
  • An association was found between increasing LDL-c polygenic score percentile and dose-dependent increase in CVD risk, among the overall cohort (test for trend, P<0.001). The 10th decile of the LDL-c polygenic score was associated with the greatest risk of CVD compared with the first decile (adjusted HR: 1.35, 95%CI 1.30-1.40, P<0.001).
  • Patients with monogenic FH had statistically significantly higher LDL-c levels compared with individuals without an FH-associated variant (mean LDL-c 161.15 [SD=49.1] vs 140.2 [SD=34.0] mg/dL, P<0.001). Monogenic FH was also associated with a statistically significantly higher risk of CVD compared with individuals without an FH-associated variant (aHR composite CVD event: 1.78, 95%CI 1.28-2.48, P<0.001). This difference was especially notable for premature CVD events at ≤55 years of age (HR: 3.17, 95%CI 1.96-5.12, P<0.001).
  • The difference in CVD risk was assessed among individuals with monogenic FH, polygenic hypercholesterolemia, or nongenetic hypercholesterolemia at comparable levels of LDL-c. Participants with monogenic FH had the highest risk for composite CVD events followed by individuals with polygenic hypercholesterolemia and those with nongenetic hypercholesterolemia (significant, stepwise trend, test for trend: HR 1.93, 95%CI 1.34-2.77, P<0.001).
  • Individuals with monogenetic FH had a significantly greater CVD risk than individuals with polygenic hypercholesterolemia (aHR 1.26, 95%CI 1.03-1.55, P=0.03). Results were similar after adjustment for LDL-c levels.
  • Among patients with monogenic FH and with severe hypercholesterolemia (LDL-c ≥193.35 mg/dL), 34.3% (12 of 35) were not receiving cholesterol-lowering medication and 40.0% (14 of 35) were unaware of their high LDL-c level at the time of enrollment. In individuals with severe hypercholesterolemia who did not have monogenic FH, 71.7% (1426 of 1990) were not receiving cholesterol-lowering medication and 75.4% (1521 of 1990) were unaware of their high LDL-c level at enrollment.


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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