Iron status and sarcopenia-related traits: a bi-directional Mendelian randomization study

Abstract

Although serum iron status and sarcopenia are closely linked, the presence of comprehensive evidence to establish a causal relationship between them remains insufficient. The objective of this study is to employ Mendelian randomization techniques to clarify the association between serum iron status and sarcopenia. We conducted a bi-directional Mendelian randomization (MR) analysis to investigate the potential causal relationship between iron status and sarcopenia. MR analyses were performed using inverse variance weighted (IVW), MR-Egger, and weighted median methods. Additionally, sensitivity analyses were conducted to verify the reliability of the causal association results. Then, we harvested a combination of SNPs as an integrated proxy for iron status to perform a MVMR analysis based on IVW MVMR model. UVMR analyses based on IVW method identified causal effect of ferritin on appendicular lean mass (ALM, β = - 0.051, 95% CI - 0.072, - 0.031, p = 7.325 × 10^-07). Sensitivity analyses did not detect pleiotropic effects or result fluctuation by outlying SNPs in the effect estimates of four iron status on sarcopenia-related traits. After adjusting for PA, the analysis still revealed that each standard deviation higher genetically predicted ferritin was associated with lower ALM (β = - 0.054, 95% CI - 0.092, - 0.015, p = 0.006). Further, MVMR analyses determined a predominant role of ferritin (β = - 0.068, 95% CI - 0.12, - 0.017, p = 9.658 × 10^-03) in the associations of iron status with ALM. Our study revealed a causal association between serum iron status and sarcopenia, with ferritin playing a key role in this relationship. These findings contribute to our understanding of the complex interplay between iron metabolism and muscle health.

Keywords: Causality; Ferritin; Iron status; Multivariable mendelian randomization; Sarcopenia.

Figure 1

An overview of the study design includes three key assumptions.MR satisfies the following three conditional assumptions: (1) there is a strong association between instrumental variables and exposure factors; (2) no confounding factors exist in the association between exposure and outcome, in other words, there is no genetic pleiotropy; and (3) the instrumental variables do not have a direct effect on outcome and can only influence outcome through exposure factors.

Figure 2

Forest plot for causal associations of iron status with ALM in UVMR analysis. Ferritin, serum iron, TIBC, TSAT are scaled to an SD increase. Effects (beta) represents change in kg ALM. IVW inverse variance weighted, WM weighted median, ALM appendicular lean mass, TIBC total iron binding capacity, TSAT transferrin saturation, CI confidence interval, UVMR univariable Mendelian randomization.

Figure 3

Forest plot for causal associations of iron status with ALM in MVMR analysis. Ferritin, serum iron, TSAT are scaled to an SD increase. Effects (beta) represents change in kg ALM. ALM appendicular lean mass, TSAT transferrin saturation, IVs numbers of instrumental variable, CI confidence interval, MVMR multivariable Mendelian randomization.