Abstract
Background: Polygenic risk scores (PRS) for cardiovascular disease (CVD) are emerging tools for risk stratification, but their interaction with modifiable lifestyle factors remains underexplored, particularly in postmenopausal women. Dietary fat quality—specifically the ratio of unsaturated to saturated fat—may modify genetic susceptibility.Methods: We analyzed data from 45,000 postmenopausal women aged 50–79 years from the Women's Health Initiative (WHI) observational study and clinical trial arms, excluding those with baseline CVD. A genome-wide PRS for coronary heart disease was constructed using summary statistics from a large GWAS. Dietary fat quality was assessed via food frequency questionnaires and categorized as low (Results: Over a median follow-up of 12.3 years, 3,450 CVD events occurred. High PRS was independently associated with increased CVD risk (HR 1.34, 95% CI 1.21–1.48). High dietary unsaturated-to-saturated fat ratio was associated with lower CVD risk (HR 0.88, 95% CI 0.82–0.95). A significant interaction was observed (p = 0.01): among women with high PRS, those with high unsaturated fat intake had a 22% lower CVD risk compared to those with low intake, while among low-PRS women the benefit was only 8%.Conclusions: PRS modifies the cardiovascular benefit of replacing saturated with unsaturated fat in postmenopausal women. Dietary recommendations for CVD prevention should consider genetic risk profiles, supporting precision nutrition approaches.