Sex Differences in the Associations of Body Composition and PPARGC1A Genetic Variants with Elevated Pulse Pressure

Background Pulse pressure (PP) is a hemodynamic marker for vascular aging. We investigated the sex-specific associations of bioelectrical impedance analysis (BIA)-derived body composition indices and PPARGC1A/VDR variants with elevated PP risk. Methods This community-based study analyzed 5,829 adults (20–90 years) from the Taiwan Biobank. Elevated PP was defined as > = 65 mmHg. Sex-stratified multiple linear regression was used to examine body composition indices. Candidate variants were screened by logistic regression and clumping, followed by the construction of a weighted genetic score (WGS). Machine-learning models and SHAP analysis were applied to evaluate the relative contributions of body composition, biochemical traits, and genetic susceptibility to elevated PP. Results FFMI was the only body composition index that remained significantly associated with PP in both females (β = 0.20, p < 0.001) and males (β = 0.09, p < 0.01) after multivariable adjustment. Adiposity-related indices (VFATL, BFR, FMI) were significant only in females. Among 946 SNPs examined across the PPARGC1A and VDR regions, three PPARGC1A variants (rs4141480, rs57677171, and rs7680511) remained significant after multiple-testing correction. A WGS derived from these variants was independently associated with elevated PP. SHAP analysis confirmed age as the dominant contributor, while FFMI ranked highly in females and WGS contributed in both sexes. Conclusions BIA-derived indices are associated with PP in a sex-specific manner, with FFMI being the most consistent marker. PPARGC1A-related genetic susceptibility independently contributes to elevated PP beyond conventional factors. Integrating body composition and genetics enhances the assessment of cardiometabolic vulnerability related to vascular aging.