# Genetic and Metabolic Factors of Familial Dysbetalipoproteinemia Phenotype: Insights from a Cross-Sectional Study

## TL;DR

This study explores how genetic and metabolic factors contribute to the development of familial dysbetalipoproteinemia, a condition linked to high cholesterol and heart disease risk.

## Contribution

The study identifies new genetic and metabolic contributors to the FD phenotype, including polygenic risk scores and metabolic syndrome components.

## Key findings

- Age, elevated polygenic risk for hypertriglyceridemia, and metabolic syndrome components are independently associated with the FD phenotype.
- Triglyceride levels are significantly linked to polygenic burden, rare lipid-related variants, and glucose metabolism disorders.
- These factors together explain 30% of triglyceride variance in a cross-validated model.

## Abstract

Familial dysbetalipoproteinemia (FD) is a prevalent and highly atherogenic hyperlipoproteinemia associated with the ε2/ε2 APOE genotype or rare APOE variants. The contributions of additional genetic and clinical factors to the FD phenotype remain unclear. We investigated these factors in both autosomal recessive and autosomal dominant forms of FD. Targeted (n = 4666) and exome (n = 194) sequencing were used to identify the ε2/ε2 APOE genotype or rare FD-causative APOE variants. Twenty-four lipid-related genes and forty variants included in a polygenic risk score for hypertriglyceridemia (HTG) were analyzed. FD was defined by the presence of FD variants and triglycerides (TG) ≥ 1.5 mmol/L (main study group). The comparison group consisted of patients with FD variants but TG < 1.5 mmol/L. Univariable and multivariable regression analyses were performed. A total of 71 unrelated subjects were identified (45.1% male, median age 50 years). FD was diagnosed in 52 patients, while 19 had FD variants only. Age (p = 0.019), elevated polygenic risk for HTG (p = 0.001), and the presence of metabolic syndrome components (p = 0.014) were independently associated with the FD phenotype. TG levels were significantly associated with polygenic burden (0.05 mmol/L per percentile), the presence of additional rare lipid-related variants (7.0 mmol/L), and glucose metabolism disorders (3.62 mmol/L), together explaining 30% of TG variance in cross-validated model. These results highlight the interplay of genetic and metabolic factors in FD development and support the integration of HTG genetic risk scores and metabolic control into personalized FD management.