Serum phosphate, BMI and Body Composition of Middle-aged and Older Adults: A Cross-sectional Association Analysis and Bi-directional Mendelian Randomization Study.

Background Observational studies have reported associations between serum phosphate and body mass index (BMI) in specific clinical settings but the nature of this relation in the general population is unclear. Objective The aim of this study was twofold: to investigate the association between serum phosphate and BMI and body composition, and to explore evidence of causality through 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 subjects aged 45-100 years from three RS cohorts. The role of serum leptin was examined in a subgroup of 1089 subjects. For MR analyses, allele scores with 6 single nucleotide polymorphisms (SNPs) for phosphate and 905 SNPs for BMI were constructed in 7983 subjects. Results Phosphate was inversely associated with BMI in the total population (β: -0.89; 95% CI: -1.17, -0.62), and stronger in females (β: -1.92; 95% CI: -2.20, -1.65) than in males (β: -0.37; 95% CI: -0.68, -0.06) (P-interaction Conclusion 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 females than in males. Adjusting for leptin attenuated this relation in females 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.