Iron status and obesity-related traits: A two-sample bidirectional Mendelian randomization study

BACKGROUND: The association between iron status and obesity-related traits is well established by observational studies, but the causality is uncertain. In this study, we performed a two-sample bidirectional Mendelian randomization analysis to investigate the causal link between iron status and obesity-related traits. METHODS: The genetic instruments strongly associated with body mass index (BMI), waist-hip ratio (WHR), serum ferritin, serum iron, transferrin saturation (TSAT), and total iron-binding capacity (TIBC) were obtained through a series of screening processes from summary data of genome-wide association studies (GWAS) of European individuals. We used numerous MR analytical methods, such as inverse-variance weighting (IVW), MR-Egger, weighted median, and maximum likelihood to make the conclusions more robust and credible, and alternate methods, including the MR-Egger intercept test, Cochran’s Q test, and leave-one-out analysis to evaluate the horizontal pleiotropy and heterogeneities. In addition, the MR-PRESSO and RadialMR methods were utilized to identify and remove outliers, eventually achieving reduced heterogeneity and horizontal pleiotropy. RESULTS: The results of IVW analysis indicated that genetically predicted BMI was associated with increased levels of serum ferritin (β: 0.077, 95% CI: 0.038, 0.116, P=1.18E-04) and decreased levels of serum iron (β: -0.066, 95% CI: -0.106, -0.026, P=0.001) and TSAT (β: -0.080, 95% CI: -0.124, -0.037, P=3.08E-04), but not associated with the levels of TIBC. However, the genetically predicted WHR was not associated with iron status. Genetically predicted iron status were not associated with BMI and WHR. CONCLUSIONS: In European individuals, BMI may be the causative factor of serum ferritin, serum iron, and TSAT, but the iron status does not cause changes in BMI or WHR.