Preprint
Association between saturated fat intake and low-density lipoprotein cholesterol across the genetic spectrum: Results from the Women’s Health Initiative
medRxiv : the preprint server for health sciences
01 Jul 2026
Abstract
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 (PGSLDL). 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 PGSLDL 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 PGSLDL group, but the association attenuated in the low PGSLDL group (P-interaction=0.01). Spline analysis revealed a non-linear interaction between PGSLDL and saturated fat, with modifying effects emerging at higher PGSLDL. Compared to individuals with low PGSLDL and low saturated fat intake, only those with both high PGSLDL 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.
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Details
- Title
- Association between saturated fat intake and low-density lipoprotein cholesterol across the genetic spectrum: Results from the Women’s Health Initiative
- Creators
- Alexa Barad - Stanford University School of MedicineVictor Ritter - Stanford University School of MedicineMatthew Nudy - Penn State Milton S. Hershey Medical CenterLinda V Van Horn - Northwestern UniversityMatthew A. Allison - University of California San DiegoCassandra N. Spracklen - University of Massachusetts AmherstLongjian Liu - Drexel University, Epidemiology and BiostatisticsSu Yon Jung - University of California, Los AngelesJoAnn E Manson - Harvard UniversityThemistocles L. Assimes - Stanford University School of MedicineMarcia L Stefanick - Stanford University School of MedicineShoa L. Clarke - Stanford University School of Medicine
- Publication Details
- medRxiv : the preprint server for health sciences
- Resource Type
- Preprint
- Language
- English
- Academic Unit
- Epidemiology and Biostatistics
- Other Identifier
- 991022199550604721