Association between saturated fat intake and low-density lipoprotein cholesterol across the genetic spectrum: Results...

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, the response to saturated fat in the diet is highly heterogeneous. Genetic factors may contribute to individual differences in response to saturated fat.

We aimed to examine whether genetic propensity for higher LDL-C modifies the association of saturated fat intake with LDL-C and incident ASCVD.

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. Models were adjusted for demographic, anthropometric, lifestyle, clinical, genetic, and technical covariates.

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 for LDL-C = 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 1.45, 95% CI 1.20-1.75). This association remained significant after further adjustment for baseline untreated LDL-C (HR 1.29, 95% CI 1.06-1.56), and evidence of an additive interaction was observed (relative excess risk due to interaction 0.37, 95% CI 0.06-0.67]).

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.