Severe hypertriglyceridemia is primarily polygenic.

Area of Science:

• Genetics
• Molecular Biology
• Cardiovascular Disease

Background:

• Hypertriglyceridemia (HTG) is a complex trait characterized by elevated plasma triglyceride levels.
• The genetic underpinnings of HTG, encompassing both monogenic and polygenic factors, remain incompletely understood.

Purpose of the Study:

• To comprehensively characterize the genetic profiles of individuals with severe HTG.
• To quantify the contributions of genetic determinants and molecular factors to severe HTG.

Main Methods:

• Conducted targeted next-generation sequencing of 73 genes and 185 SNPs related to dyslipidemia in two independent cohorts (n=563).
• Screened for rare variants in key genes (LPL, APOC2, GPIHBP1, APOA5, LMF1).
• Utilized a polygenic risk score to evaluate the impact of common variant accumulation.

Main Results:

• Combined analysis of 563 Caucasian patients revealed significant genetic susceptibility to HTG compared to controls (OR 5.77).
• 32.0% of patients exhibited an extreme accumulation of common variants (high polygenic risk), and 14.4% carried heterozygous rare variants.
• Only 1.1% of patients had biallelic rare variants, indicating monogenic HTG.

Conclusions:

• This study provides the most in-depth evaluation of genetic determinants for severe HTG to date.
• The predominant genetic feature in severe HTG is the accumulation of common variants (polygenic HTG, 46.3%), with rare variants contributing in a subset of patients.
• Monogenic HTG due to biallelic rare variants is rare (1.1%).