Elevated low density lipoprotein cholesterol (LDL-C) polygenic scores were found to be associated with higher levels of LDL-C and increased risk for atherosclerotic cardiovascular disease (ASCVD) in patients with monogenic familial hypercholesterolemia (FH), according to study results published in Circulation: Genomic and Precision Medicine.

While FH is associated with elevated LDL-C levels and increased risk for premature ASCVD, there is substantial variability in LDL-C levels between patients with FH.

The weighted LDL-C polygenic score was based on 28 single nucleotide variants, and determined in 3independent cohorts of patients with FH: the British Columbia FH (n=262); Nutrition, Metabolism and Atherosclerosis Clinic (n=552); and UK Biobank (n=306).

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A fixed-effect meta-analysis was used to assess the association between elevated LDL-C polygenic score and risk for ASCVD events (ie, myocardial infarction, cardiovascular or carotid revascularization, and stroke).

A 20% increase in LDL-C polygenic score was found to be associated with higher LDL-C levels in the Nutrition, Metabolism and Atherosclerosis Clinic (P =.0007) and UK Biobank (P =.004) cohorts, but not in the British Columbia FH cohort. In addition, the LDL-C polygenic score was found to be associated with LDL-C levels (β, 0.13; 95% CI, 0.072–0.19 per 20% increase in LDL-C polygenic score; P <.0001) in a meta-analysis.

In all 3 cohorts, a LDL-C polygenic score in the 80th percentile or higher was associated with a trend towards increased risk for ASCVD, effect which was significant in the meta-analysis (hazard ratio, 1.48; 95% CI, 1.02-2.14; P =.04).

Study limitations include the use of a limited LDL-C polygenic score and of different approaches to determine baseline lipid profile, and a predominantly European cohort, which may limit the generalizability of lipid polygenic scores.

“Our results suggest that there may be utility in broader genetic testing strategies, that go beyond candidate genes, to improve the risk stratification of individuals with monogenic FH,” concluded the researchers.


Trinder M, Paquette M, Cermakova L, Ban et al. Polygenic contribution to low-density lipoprotein cholesterol levels and cardiovascular risk in monogenic familial hypercholesterolemia. Circ Genom Precis Med. 2020 Oct;13(5):515-523. doi: 10.1161/CIRCGEN.120.002919

This article originally appeared on Endocrinology Advisor