Association between saturated fat intake and low-density lipoprotein cholesterol across the genetic spectrum: Results from the Women's Health Initiative

Background: Elevated low-density lipoprotein cholesterol (LDL-C) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Guidelines recommend reducing saturated fat intake to lower LDL-C. However, LDL-C responses to saturated fat vary substantially from person to person. Genetic factors may contribute to individual differences in response to saturated fat. Objectives: We aimed to examine whether genetic propensity for higher LDL-C modifies the association of saturated fat intake with LDL-C and incident ASCVD. Methods: We studied 20,940 genotyped postmenopausal women from the Women's Health Initiative. Exposures included saturated fat intake (percentage of total calories) derived from food frequency questionnaires and a genome-wide polygenic score for LDL-C (PGS-LDL). The primary outcome was LDL-C. The secondary outcome was incident ASCVD. Associations were assessed using multivariable linear and Cox regressions. Effect modification was evaluated using interaction terms and restricted cubic spline analyses. Results: The median LDL-C at baseline for participants with PGS-LDL below and above the median was 135 mg/dL [Q1: 114, Q3: 160] and 162 mg/dL [137, 188], respectively. Saturated fat intake was positively associated with LDL-C in the high PGS-LDL group, but the association attenuated in the low PGS-LDL group (P-interaction=0.01). Spline analysis revealed a non-linear interaction between PGS-LDL and saturated fat, with modifying effects emerging at higher PGS-LDL. Compared to individuals with low PGS-LDL and low saturated fat intake, only those with both high PGS-LDL and high saturated fat intake had increased risk for ASCVD in an adjusted analysis (HR 1.30, 95% CI 1.13-1.51). This association remained significant after further adjustment for baseline LDL-C (HR 1.17, 95% CI 1.01-1.37). Spline analyses of ASCVD risk revealed a similar interaction pattern to that observed for LDL-C. Conclusions: These findings suggest that the association between saturated fat intake and LDL-C and subsequent ASCVD risk may be stronger for individuals with a genetic propensity towards high LDL-C.