Causal association between iron status and heart failure: A 2-sample bidirectional Mendelian randomization study.

Area of Science:

• Cardiovascular Research
• Genetic Epidemiology
• Iron Metabolism

Background:

• Observational studies suggest a link between serum iron status and heart failure (HF).
• Confounding factors and reverse causation create uncertainty about a causal relationship.
• Genetic approaches are needed to clarify the association between iron status and HF risk.

Purpose of the Study:

• To investigate the causal relationship between genetically predicted serum iron status and heart failure (HF).
• To assess whether serum ferritin, serum iron, total iron-binding capacity, and transferrin saturation causally influence HF risk.

Main Methods:

• Mendelian Randomization (MR) analysis using inverse variance weighting, MR-Egger, and weighted median methods.
• Sensitivity analyses including MR-Egger intercept test, MR-pleiotropy residual sum and outliers (MR-PRESSO), Cochran Q test, and leave-one-out analysis.
• Reverse MR analysis to assess potential reverse causality.

Main Results:

• Elevated serum ferritin levels demonstrated a causal relationship with a reduced risk of HF (OR=1.147, P=0.029).
• No significant genetic causal relationship was found between serum iron, total iron-binding capacity, transferrin saturation, and HF.
• Sensitivity analyses and reverse MR analysis confirmed the robustness and lack of pleiotropy or reverse causality.

Conclusions:

• Genetically predicted higher serum ferritin levels are causally associated with a lower risk of heart failure.
• Serum ferritin may act as a protective factor against HF development.
• Other iron status markers (serum iron, TIBC, TSAT) do not show a causal link to HF risk in this MR study.