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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.

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Background Hypertriglyceridemia is associated with increased risk of coronary heart disease but the association is often attributed to concomitant metabolic abnormalities. We investigated the epidemiology of primary isolated hypertriglyceridemia (PIH) and associated cardiovascular risk in a population‐based setting. Methods and Results We identified adults with at least one triglyceride level ≥500 mg/dL between 1998 and 2015 in Olmsted County, Minnesota. We also identified age‐ and sex‐matched controls with triglyceride levels <150 mg/dL. There were 3329 individuals with elevated triglyceride levels; after excluding those with concomitant hypercholesterolemia, a secondary cause of high triglycerides, age <18 years or an incomplete record, 517 patients (49.4±14.0 years, 72.0% men) had PIH (triglyceride 627.6±183.6 mg/dL). The age‐ and sex‐adjusted prevalence of PIH in adults was 0.80% (0.72–0.87); the diagnosis was recorded in 60%, 46% were on a lipid‐lowering medication for primary prevention and a triglyceride level <150 mg/dL was achieved in 24.1%. The association of PIH with coronary heart disease was attenuated but remained significant after adjustment for demographic, socioeconomic, and conventional cardiovascular risk factors (hazard ratio [HR], 1.53; 95% CI, 1.06‐2.20; P = 0.022). There was no statistically significant association between PIH and cerebrovascular disease (HR, 1.06; 95% CI, 0.65‐1.73, P = 0.813), peripheral artery disease (HR, 1.27; 95% CI, 0.43‐3.75; P = 0.668), or the composite end point of all 3 (HR, 1.28; 95% CI, 0.92‐1.80; P =0.148) in adjusted models. Conclusions PIH was associated with incident coronary heart disease events (although there was attenuation after adjustment for conventional risk factors), supporting a causal role for triglycerides in coronary heart disease. The condition is relatively prevalent but awareness and control are low.

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