Serum Phosphate, BMI, and Body Composition of Middle-Aged and Older Adults: A Cross-Sectional Association Analysis and Bidirectional Mendelian Randomization Study

Background: Observational studies have reported associations between serum phosphate and BMI in specific clinical settings, but the nature of this relation in the general population is unclear. Objectives: The aim of this study was twofold: to investigate the association between serum phosphate and BMI and body composition, as well as to explore evidence of causality through a bidirectional one-sample Mendelian randomization (MR) in the population-based Rotterdam Study (RS). Methods: Observational associations between phosphate (mg/dL) and BMI, lean mass, and fat percentage (fat%), estimated by DXA, were analyzed using multivariable regression models in 9202 participants aged 45-100 y from 3 RS cohorts. The role of serum leptin was examined in a subgroup of 1089 participants. For MR analyses, allele scores with 6 single-nucleotide polymorphisms (SNPs) for phosphate and 905 SNPs for BMI were constructed in 7983 participants. Results: Phosphate was inversely associated with BMI in the total population (β: -0.89; 95% CI: -1.17, -0.62), and stronger in women (β: -1.92; 95% CI: -2.20, -1.65) than in men (β: -0.37; 95% CI: -0.68, -0.06) (P-interaction < 0.05). Adjustment for leptin did not change results in men. In women, adjustment for leptin attenuated the association, but it was not abolished (β: -0.94; 95% CI: -1.45, -0.42). Phosphate was inversely associated with fat%, but not with lean mass, in both sexes. MR analyses suggested a causal effect of BMI on serum phosphate (β: -0.01; 95% CI: -0.02, 0.00) but not vice versa. Conclusions: Serum phosphate was inversely associated with BMI and fat% in a population-based study of middle-aged and older adults, with a stronger effect in women than in men. Adjusting for leptin attenuated this relation in women only. MR results suggest a causal effect of BMI on phosphate but not vice versa. An underlying sex dimorphism in phosphate homeostasis should be further explored.