Polygenic Risk, Modifiable Lifestyle Behaviors, and Metabolic Factors: Associations with HDL-C, Triglyceride Levels, and Cardiovascular Risk

Background/Objective: Dyslipidemia significantly contributes to cardiovascular disease (CVD), with triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) as key components. While genetics play a key role in lipid levels, the interplay between genetic predisposition and modifiable lifestyle factors remains unexplored in population-based studies. We aimed to study the associations between weighted polygenic risk scores (wPRS) for TG and HDL-C, lifestyle, and metabolic factors with lipid traits and CVD. Methods: In this cross-sectional study, genotype, metabolic and lifestyle data from an Israeli cohort (n = 5584 adults) were analyzed. Individual wPRSs were constructed for TG and HDL-C based on SNPs associated with each trait. Gene-environment (lifestyle and metabolic factors) associations were evaluated by stratifying participants into high wPRS (≥90th percentile) vs. lower wPRS (<90th percentile). Results: High wPRSs were significantly associated with unfavorable lipid profiles (higher TG and lower HDL-C) and elevated TG/HDL-C ratios. Males and females in the high wPRS_HDL had 97- and 10-fold higher odds of CVD, respectively (p < 0.0001). Individuals with a combined high wPRS_HDL and wPRS_TG showed a 44-fold increase in CVD odds (p < 0.0001). Obesity (BMI > 30) and HbA1c ≥5.7% were significantly associated with elevated TG and reduced HDL-C levels, particularly in high wPRS_HDL and WPRS_TG individuals, while moderate wine (1–3 drinks/week) consumption and coffee intake (≥1 cup/day) mitigated these effects, particularly among individuals with high wPRS. Conclusions: Risk stratification based on genetic, lifestyle and metabolic profiles may inform personalized prevention strategies for dyslipidemia.