Genetic Etiology of Hypercholesterolemia May Affect CVD Risk

Familial hypercholesterolemia
Genetic research abstract – Familial hypercholesterolemia
Individuals with hypercholesterolemia without an identifiable genetic cause may be at a relatively lower risk for CVD than those with monogenic or polygenic etiologies.

Patients with monogenic familial hypercholesterolemia (FH) may be at the greatest risk for cardiovascular disease (CVD) among individuals with FH, followed by those polygenic hypercholesterolemia, according to study results published in JAMA Cardiology. Furthermore, patients with hypercholesterolemia without an identifiable genetic cause may be at a relatively lower risk for CVD.

Previous studies have shown that monogenic FH-associated pathogenic variants in the LDLR or PCSK9 genes are associated with a 2- to 3.5-fold increased CVD risk compared with elevated low-density lipoprotein cholesterol (LDL-C) levels that are not associated with a genetic variant. Polygenic hypercholesterolemia may account for approximately 20% to 30% of patients with a phenotype of clinical FH but without an identified FH-associated variant. The goal of the current study was to explore the association between monogenic and polygenic causes of hypercholesterolemia and the risk for CVD.

The study included adults aged 40 to 69 years from the UK Biobank, recruited between March 13, 2006, and October 1, 2010, and followed up until March 31, 2017.

Of 502,543 individuals in the UK Biobank cohort, 48,741 had available genotyping array and exome sequencing data, including 277 participants with monogenic FH (0.57% prevalence), 2379 with polygenic hypercholesterolemia, and 2232 with hypercholesterolemia without an identifiable genetic cause.

Related Articles

The risk for atherosclerotic CVD events was significantly greater in the group of patients with monogenic FH compared with those without a monogenic FH-associated variant (adjusted hazard ratio [aHR], 1.78; 95% CI, 1.28-2.48; P <.001), and this risk was even greater for premature CVD events occurring at ≤55 years of age (aHR, 3.17; 95% CI, 1.96-5.12; P <.001).

Among individuals with comparable levels of LDL-C, there was a stepwise trend observed for CVD risk in the 3 patient groups. Monogenic FH was associated with a greater CVD risk compared with polygenic hypercholesterolemia (aHR, 1.26; 95% CI, 1.03-1.55; P =.03) and hypercholesterolemia without an identifiable genetic cause (aHR, 1.93; 95% CI, 1.34-2.77; P <.001).

The researchers acknowledged several study limitations, including lack of data on LDL-C-lowering medication or family history of CVD. In addition, the cohort was limited to individuals with British white genetic ancestry.

“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,” concluded the researchers.

Follow @EndoAdvisor


Trinder M, Francis GA, Brunham LR. Association of monogenic vs polygenic hypercholesterolemia with risk of atherosclerotic cardiovascular disease [published online February 12, 2020]. JAMA Cardiol. doi:10.1001/jamacardio.2019.5954