Among 20,940 postmenopausal women in the Women's Health Initiative, saturated fat intake was positively associated with LDL-C only in those with a high polygenic score for LDL-C (PGS-LDL), while the association largely attenuated in the low-genetic-risk group (P-interaction=0.01). Critically, only women carrying both high PGS-LDL and high saturated fat intake faced a 30% greater ASCVD risk (HR 1.30, 95% CI 1.13–1.51) versus low-risk, low-intake counterparts — a signal that persisted after adjusting for baseline LDL-C (HR 1.17, 95% CI 1.01–1.37), suggesting a mechanism partly independent of LDL elevation alone.
This preprint, not yet peer-reviewed, adds meaningful precision to a decades-old dietary debate. Current guidelines uniformly recommend saturated fat reduction for cardiovascular protection, yet population-level effect sizes have always been modest and heterogeneous. This large, well-characterized cohort now suggests that dietary saturated fat may function more as a conditional risk factor — consequential primarily when genetic LDL-raising propensity is already elevated. That reframing aligns with emerging nutrigenomics research but stops short of proving causality in a non-randomized design. Key limitations include the all-female, postmenopausal cohort limiting generalizability to men and younger adults, reliance on food frequency questionnaires for dietary assessment, and observational confounding. If confirmed, these findings could support genotype-informed dietary counseling, prioritizing saturated fat restriction for high-PGS individuals while relaxing blanket recommendations for genetic low-responders — a potentially paradigm-shifting shift toward precision nutrition in cardiology.
