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

Zengyuan Zhou, Hanyu Zhang, Ke Chen, Changqi Liu, Zengyuan Zhou, Hanyu Zhang, Ke Chen, Changqi Liu

Abstract

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.

Keywords: Mendelian randomization; iron status; obesity-related traits; serum ferritin; serum iron; transferrin saturation.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2023 Zhou, Zhang, Chen and Liu.

Figures

Figure 1
Figure 1
A flow diagram of the process in the current Mendelian randomization analysis.
Figure 2
Figure 2
Forest plots of Mendelian randomization analyses of the association between genetically predicted iron status and obesity-related traits. (A) serum ferritin – BMI and WHR; (B) serum iron – BMI and WHR; (C) TIBC – BMI and WHR; (D) TSAT - BMI and WHR. Data are expressed as raw β with 95% CI. IVW, inverse variance–weighted method; fe, fixed effects model; re, multiplicative random effects model; BMI, body mass index; WHR, waist-hip ratio; TIBC, total iron-binding capacity; TSAT, transferrin saturation.
Figure 3
Figure 3
Forest plots of Mendelian randomization analyses of the association between genetically predicted iron status and obesity-related traits. (A) BMI - serum ferritin, serum iron, TIBC and TSAT; (B) WHR - serum ferritin, serum iron, TIBC and TSAT. Data are expressed as raw β with 95% CI.
Figure 4
Figure 4
Scatter plots of Mendelian randomization analyses of the association between genetically predicted obesity-related traits and iron status. (A) BMI - serum ferritin, serum iron, TIBC and TSAT; (B) WHR - serum ferritin, serum iron, TIBC and TSAT.
Figure 5
Figure 5
Scatter plots of Mendelian randomization analyses of the association between genetically predicted iron status and obesity-related traits. (A) serum ferritin – BMI and WHR; (B) serum iron – BMI and WHR; (C) TIBC – BMI and WHR; (D) TSAT - BMI and WHR.

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