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

Abstract

ABSTRACT 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.