Genetic basis of hypercholesterolemia in adults

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.

Fig. 1. Selection of the study cohort.

ALP alkaline phosphatase, BSA body surface area, Cr creatinine, DLCN Dutch lipid clinic network, GFR glomerular filtration rate, LDL-C low-density lipoprotein cholesterol, TSH thyroid stimulating hormone.

Fig. 2. Distribution of LDL-C levels in the study population.

a Distribution of LDL-C levels based on genotype, and b based on phenotype. The boxplots are embedded in the density plots. The central line represents median, box limits represent upper and lower quartiles, the vertical lines represent 1.5× quartile range, and points represent outliers. In the left plot, PGS1–9 indicates those with the PGS in the 1st to 9th decile. PGS10 represents those with the PGS in the top decile (polygenic etiology of hypercholesterolemia) and Monogenic represents those with a P/LP variant in LDLR, APOB or PCSK9. On the right side, DLCN criteria are used for categorizing cases as Unlikely FH: DLCN <3, Possible FH: 3 ≤ DLCN <6, and Probable/Definite FH: DLCN ≥6. FH familial hypercholesterolemia, LDL-C low-density lipoprotein cholesterol, PGS polygenic score (number refers to PGS decile). t-test is used for comparison. *P-value < 0.05, **P-value < 0.01, ***P-value < 0.001, ****P-value < 0.0001 and ns = non-significant.

Fig. 3. Overlap of monogenic/polygenic FH and FH ascertained by clinical criteria.

a Proportion of individuals in FH phenotypic categories who had an identifiable genetic etiology. b Proportion of individuals with polygenic or monogenic etiology for hypercholesterolemia who met the clinical criteria for FH. c Proportion of individuals in different LDL level who had an identifiable genetic etiology. d Proportion of individuals in different LDL percentiles who had an identifiable genetic etiology. FH familial hypercholesterolemia, LDL-C low-density lipoprotein cholesterol, PGS polygenic score. PGS1–9 indicates those with the PGS in the 1st to 9th decile. PGS10 represents those with the PGS in the top decile (polygenic etiology of hypercholesterolemia) and Monogenic represents those a P/LP variant in LDLR, APOB or PCSK9. DLCN criteria are used for the categorization of cases as Unlikely FH: DLCN <3, Possible FH: 3 ≤ DLCN <6, and Probable/Definite FH: DLCN ≥6.

Fig. 4. Distribution of monogenic etiology across categories of DLCN score and corresponding LDL-C levels.

Cases with P/LP APOB or PCSK9 variants are labeled and the remaining had P/LP LDLR variants. DLCN Dutch lipid clinic network, FH familial hypercholesterolemia, LDL-C low-density lipoprotein cholesterol.