Monogenic Hypercholesterolemia Increases Cardiovascular Disease Risk

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' hypercholesterolemia has a polygenic rather than a monogenic cause, and it is unclear if polygenic variants also alter the risk of CVD. Polygenic hypercholesterolemia is estimated to account for approximately 20% to 30% of patients with clinical FH. The risk of CVD for individuals with polygenic hypercholesterolemia likely depends on the reference group.


A team of scientists from University of British Columbia (Vancouver, BC, Canada) conducted a genetic-association case-control cohort study on 48,741 individuals who were recruited by the UK Biobank, using genotyping array and exome sequencing data to identify individuals with monogenic or polygenic hypercholesterolemia. They assessed whether any genetic variant for hypercholesterolemia altered the risk of atherosclerotic CVD, and evaluated how this risk compared with that of nongenetic hypercholesterolemia.

Serum biochemistry assays were conducted on a Beckman Coulter AU5800 analyzer (Beckman Coulter, High Wycombe, UK) or for the glycated hemoglobin (HbA1c) by High Performance Liquid Chromatography using Bio-Rad Variant II Turbo analyzers (Bio-Rad Laboratories, Hercules, CA, USA). 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.

The team reported a monogenic cause for hypercholesterolemia was found in 277 participants and a polygenic cause in 2,379 participants. Overall, monogenic FH-associated variants were found in the LDLR gene for 257 individuals, in PCSK9 for 13 individuals, and in APOB for seven individuals. They identified a total of 121 unique monogenic FH-associated variants, most of which were in LDLR. Both polygenic and monogenic causes of hypercholesterolemia appeared to be associated with an increased risk of CVD compared with hypercholesterolemia with an undetermined cause. However, monogenic hypercholesterolemia was associated with the greatest risk of CVD.

The authors concluded that monogenic FH and polygenic hypercholesterolemia were associated with an increased CVD risk compared with hypercholesterolemia without an identifiable genetic cause, with monogenic FH associated with the greatest risk. These results suggest that a possible genetic cause of hypercholesterolemia is associated with CVD risk and underscores the importance of genetic profiling to better stratify risk in patients. The study was published on February 12, 2020 in the journal JAMA Cardiology.

Related Links:
University of British Columbia
Beckman Coulter
Bio-Rad Laboratories