Body fat percentage and hypertension risk: A population-based observational and Mendelian randomization study

This study aimed to investigate the association and potential causal relationship between body fat percentage (BFP) and hypertension, with a focus on sex-specific thresholds and clinical implications for prevention. We integrated data from the National Health and Nutrition Examination Survey (1999-2018; n = 25,957) and summary-level genome-wide association studies (GWAS) from United Kingdom Biobank and Finnish Genetic Epidemiology Consortium. Multivariate logistic regression, restricted cubic spline, and threshold effect analyses were used to evaluate the nonlinear association between BFP and hypertension in the observational cohort. Two-sample Mendelian randomization (MR) employed single-nucleotide polymorphisms as instrumental variables, with inverse-variance weighted as the primary method; sensitivity analyses (MR-Egger, leave-one-out, heterogeneity tests) assessed robustness. Hypertension prevalence increased progressively from adipopenia (6.5%) to obesity (43.1%). Restricted cubic spline revealed a nonlinear positive association between BFP and hypertension in both sexes (P < .001 for nonlinearity). Sex-specific inflection points were identified: 31.32% in males and 41.82% in females. Below these thresholds, each 1% increase in BFP conferred higher odds of hypertension (males: odds ratio [OR] = 1.10; females: OR = 1.16); the effect attenuated above the thresholds. MR analyses confirmed a causal effect of genetically predicted BFP on hypertension (United Kingdom Biobank: OR = 1.003, 95% confidence interval: 1.001-1.005, P < .001; Finnish Genetic Epidemiology Consortium: OR = 1.846, 95% confidence interval: 1.587-2.146, P < .001), with no evidence of heterogeneity or horizontal pleiotropy. Higher BFP is robustly associated with and likely causally contributes to increased hypertension risk, with distinct sex-specific thresholds. These findings support incorporating BFP (beyond body mass index) into hypertension risk assessment and personalized prevention strategies.