THE RELATION BETWEEN PHOSPHATE AND BMI AND BODY COMPOSITION IN THE ROTTERDAM STUDY: A BIDIRECTIONAL MENDELIAN RANDOMIZATION STUDY

Objectives: Observational studies have reported associations between serum phosphate (P) and body mass index (BMI) in specific settings (such as morbid obesity and hypertension) but the nature of this relation in the general population is unclear. This study aimed to investigate whether P and BMI and body composition are related and to explore evidence of causality in these associations through bidirectional one-sample Mendelian Randomization (MR).

Methods: 9633 subjects from three cohorts from the population-based Rotterdam Study were included for phenotypic analyses and 8378 subjects were included for MR analyses. Age-adjusted results were meta-analyzed. Outcomes were BMI, waist-to-hip ratio, fat mass, lean mass and fat%, estimated by DXA. Subgroup analysis adjusted for leptin levels was performed. For MR, allele scores with 5 single nucleotide polymorphisms (SNPs) for P and 905 SNPs for BMI were constructed.

Results: An inverse association between P (mg/dL) and BMI was found in both genders (β (95% CI): men: -0.41 (-0.76 to -0.05), p=0.02; women: -1.98 (-2.26 to -1.71), p<0.001), with a significant sex-interaction. Results were not explained by potential confounders. Adjustment for leptin attenuated but did not abolish this relation in women. There was a negative relation with fat percent and fat mass in both sexes, but the latter was abolished in men after adjusting for estradiol and testosterone. Age and gender adjusted MR analyses strongly suggests a borderline causal effect of genetically determined BMI on phosphate (β (95% CI):-0.01 (-0.02 to 0.00), p=0.05).

Conclusion: In our study, P was negatively associated with BMI and body fatness with a stronger effect in women compared to men. Leptin partially explained this relation in women. MR analysis suggests a causal effect of BMI on P. Our results suggest an underlying gender dimorphism in P homeostasis that should be further explored due to its potential implications.