Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia

Area of Science:

• Genetics
• Cardiovascular Disease
• Metabolic Disorders

Background:

• Combined hyperlipidemia (CHL) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels.
• The genetic underpinnings of CHL remain largely undefined despite extensive research.

Purpose of the Study:

• To elucidate the genetic architecture of CHL by comparing genetic profiles.
• To differentiate CHL's genetic basis from isolated hypercholesterolemia and isolated hypertriglyceridemia (HTG).

Main Methods:

• Targeted DNA sequencing was performed on patients with CHL, isolated hypercholesterolemia, and isolated HTG.
• Analysis included rare variants in lipid metabolism genes and polygenic scores for LDL-C and TG.
• Genetic profiles were compared against 1000 Genomes Project controls.

Main Results:

• CHL and isolated HTG patients exhibited significantly higher odds of a high polygenic score for TG.
• CHL patients showed no significant accumulation of rare variants for LDL-C or TG, nor a high LDL-C polygenic score.
• Isolated hypercholesterolemia patients had increased odds of rare variants linked to familial hypercholesterolemia, while isolated HTG patients had increased odds of rare variants linked to severe HTG.

Conclusions:

• Combined hyperlipidemia (CHL) demonstrates a genetic profile similar to isolated hypertriglyceridemia (HTG), a known polygenic trait.
• Both CHL and isolated HTG cohorts showed an accumulation of common variants associated with elevated TG.
• Elevated LDL-C levels in CHL are not associated with common or rare genetic variants related to LDL-C metabolism.