Familial combined hyperlipidemia is a polygenic trait

Area of Science:

• Genetics
• Cardiovascular Disease
• Metabolic Disorders

Background:

• Familial combined hyperlipidemia (FCH) is characterized by elevated plasma triglyceride (TG) and low-density lipoprotein (LDL) cholesterol.
• Despite extensive research for nearly 50 years, a single causative gene for FCH has not been identified.

Purpose of the Study:

• To review the genetic basis of Familial Combined Hyperlipidemia (FCH).
• To summarize recent findings on the genetic architecture of FCH.
• To outline future research directions for understanding FCH etiology.

Main Methods:

• Review of recent genetic studies utilizing next-generation sequencing and analytic methods.
• Analysis of genetic profiling data from patients with FCH and hypertriglyceridemia.

Main Results:

• Recent studies confirm a polygenic basis for FCH, driven by common single nucleotide polymorphisms (SNPs) of small-to-moderate effect.
• Rare monogenic variants, like those in familial hypercholesterolemia, play a minimal role in FCH.
• Patients with FCH and hypertriglyceridemia share a similar polygenic basis with multiple TG-raising common SNPs.

Conclusions:

• The genetic susceptibility to FCH is predominantly polygenic.
• Future research requires larger, ancestrally diverse cohort studies.
• Investigating ancestry-specific polygenic scores, epigenetic, and lifestyle factors is crucial for defining FCH etiology.