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