Abstract
We investigated monogenic and polygenic causes of hypercholesterolemia in a population-based cohort, excluding secondary hypercholesterolemia, and using an established framework to identify pathogenic variants. We studied 1682 individuals (50.2 ± 8.6 years, 41.3% males) from southeast Minnesota with primary hypercholesterolemia (low-density lipoprotein cholesterol (LDL-C) ≥155 mg/dl in the absence of identifiable secondary causes). Familial hypercholesterolemia (FH) phenotype was defined as a Dutch Lipid Clinic Network (DLCN) score ≥6. Participants underwent sequencing of LDLR, APOB, and PCSK9, and genotyping of 12 LDL-C-associated single-nucleotide variants to construct a polygenic score (PGS) for LDL-C. The presence of a pathogenic/likely pathogenic variant was considered monogenic etiology and a PGS ≥90th percentile was considered polygenic etiology. The mean LDL-C level was 187.3 ± 32.3 mg/dl and phenotypic FH was present in 8.4% of the cohort. An identifiable genetic etiology was present in 17.1% individuals (monogenic in 1.5% and polygenic in 15.6%). Phenotypic and genetic FH showed poor overlap. Only 26% of those who met the clinical criteria of FH had an identifiable genetic etiology and of those with an identifiable genetic etiology only 12.9% met clinical criteria for FH. Genetic factors explained 7.4% of the variance in LDL-C. In conclusion, in adults with primary hypercholesterolemia, 17.1% had an identifiable genetic etiology and the overlap between phenotypic and genetic FH was modest.
Highlights
Hypercholesterolemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD)[1,2]
The mean low-density lipoprotein cholesterol (LDL-C) level in carriers of Pathogenic/likely pathogenic (P/LP) variants was 232.04 ± 54.78 mg/dl, significantly higher than those with polygenic score (PGS) >90th percentile, which in turn was higher than in those without these two conditions (185.72 ± 31.20 mg/dl; P-value < 0.01). (Fig. 2) There were no significant differences between triglyceride and highdensity lipoprotein cholesterol levels between these three categories (Supplementary Fig. 3)
When participants were categorized based on their age-sex-specific LDL-C percentile, monogenic etiology of familial hypercholesterolemia (FH) was present in 2.6% and 4.8% of those with LDL-C ≥95th (n = 818) and ≥99th (n = 372) percentile, respectively
Summary
Hypercholesterolemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD)[1,2]. It is estimated that 95 million U.S adults age 20 or older have an elevated cholesterol level with only half on lipid-lowering treatment[3]. Both genetic and lifestyle factors are known to predispose to hypercholesterolemia[4,5]. The reported prevalence of monogenic and polygenic etiology in such cohorts ranged from 1.7%–50% and 20%–30%, respectively[6,7,8,9,10,11,12,13,14,15] These estimates are affected by the referral bias inherent in such cohorts, inclusion of individuals with secondary forms of hypercholesterolemia, and variable application of guidelines to ascertain pathogenic variants in FH genes
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