Individuals with monogenic or polygenic familial hypercholesterolemia (FH) were found to be at an elevated risk for atherosclerotic cardiovascular disease (ASCVD) compared with those with nongenetic hypercholesterolemia, according to study results published in JAMA Cardiology.

Although monogenic FH and increased low-density lipoprotein cholesterol (LDL-C) levels have been associated with an increased risk for ASCVD risk, many patients have a polygenic form of hypercholesterolemia, for which the ASCVD risk remains unknown.

In this prospective, genetic-association, case-control cohort study, 48,741 adults (aged 40-69 years; mean age, 56.6±8.0 years; 54.5% women) were recruited by the United Kingdom Biobank between March 2006 and October 2010, with follow-up through March 2017. Patients were identified as having monogenic (LDLR, APOB, and PCSK9), polygenic (LDL-C polygenic score >95th percentile using 223 cohort-wide single nucleotide variants), or nongenetic hypercholesterolemia, based on Biobank genotyping arrays and exome sequencing data.


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ASCVD clinical outcomes examined were incident myocardial infarction, ischemic stroke, coronary/carotid revascularization, and all-cause mortality rates.

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In this cohort, 277individuals (0.57%) had monogenic FH, 2379 patients (4.88%) had polygenic hypercholesterolemia, and 2232 individuals (4.58%) had nongenetic hypercholesterolemia. Participants with vs without monogenic FH were found to be at increased risk for an ASCVD event before 55 years of age (6.1% vs 2.0%, respectively; adjusted hazard ratio [aHR], 3.17; 95% CI, 1.96-5.12; P <.001). Individuals with monogenic or polygenic variants had higher risks for ASCVD events compared with the general population.

At comparable baseline LDL-C levels, participants with monogenic or polygenic FH and polygenic hypercholesterolemia were found to be greater risk for ASCVD events compared with patients with nongenetic hypercholesterolemia (HR, 1.93; 95% CI, 1.34-2.77; P <.001 and HR, 1.26; 95% CI, 1.03-1.55; P =.03, respectively).

Study limitations include a lack of assessment of LDLR copy number and of larger insertion/deletion variants, an underrepresentation of nonwhite non-European populations in the cohort, and the lack of information on cholesterol-lowering medication.

“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,” noted the authors. They recommended that future research explore FH phenotypic modulation via genetic background and environmental factors.

Reference

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