Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia

BACKGROUND: Combined hyperlipidemia (CHL) is a common disorder defined by concurrently elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels. Despite decades of study, the genetic basis of CHL remains unclear. OBJECTIVE: To characterize the genetic profiles of patients with CHL and compare them to those in patients with isolated hypercholesterolemia and isolated hypertriglyceridemia (HTG). METHODS: DNA from 259, 379 and 124 patients with CHL, isolated hypercholesterolemia and isolated HTG, respectively, underwent targeted sequencing. We assessed: 1) rare variants disrupting canonical LDL-C or TG metabolism genes; and 2) two polygenic scores-for elevated LDL-C and TG-calculated using common trait-associated single-nucleotide polymorphisms (SNPs). Genetic profiles were compared against 1000 Genomes Project controls. RESULTS: Both CHL and isolated HTG patients had significantly increased odds of a high polygenic score for TG: 2.50 (95% confidence interval [CI] 1.61-3.88; P < 0.001) and 3.72 (95% CI 2.24-6.19; P < 0.001), respectively. CHL patients had neither a significant accumulation of rare variants for LDL-C or TG, nor a high polygenic score for LDL-C. In contrast, patients with isolated hypercholesterolemia had a 3.03-fold increased odds (95% CI 2.22-4.13; P < 0.001) of carrying rare variants associated with familial hypercholesterolemia, while patients with isolated HTG had a 2.78-fold increased odds (95% CI 1.27-6.10; P = 0.0136) of carrying rare variants associated with severe HTG. CONCLUSION: CHL is genetically similar to isolated HTG, a known polygenic trait. Both cohorts had a significant accumulation of common TG-raising variants. Elevated LDL-C levels in CHL are not associated with common or rare LDL-C-related genetic variants.