Exploring the Causal Relationship Between Inflammatory Cytokines and MRI‐Derived Brain Iron: A Mendelian Randomization Study

ABSTRACT Background The association between inflammation and brain iron deposition is widely acknowledged. However, the precise causal impact of peripheral inflammatory cytokines on changes in brain iron content remains uncertain. Methods The study utilized an available genome‐wide association study (GWAS) summary associated with inflammatory cytokines from The Cardiovascular Risk in Young Finns Study and the FINRISK surveys. The GWAS data for brain iron markers were obtained from the UK Biobank. We assessed the iron content of each brain region using susceptibility‐weighted magnetic resonance imaging, utilizing both quantitative susceptibility mapping and T2* measurements. The primary outcomes were susceptibility ( χ ) and T2*, which serve as indices of iron deposition. To investigate the causal relationship between exposure and outcome, we primarily employed inverse variance weighting, MR Egger, weighted median, simple mode, and weighted mode methods, collectively enhancing the robustness of our results. Results The results of MR analyses demonstrate that our study unveiled that nerve growth factor‐β, hepatocyte growth factor, interleukin‐1 (IL‐1), IL‐8, macrophage inflammatory protein 1α, and tumor necrosis factor‐α were associated with elevated brain iron content in the regions of left hippocampus, putamen, left thalamus, right pallidum, right hippocampus, left amygdala, respectively. Furthermore, our investigation provides evidence for a negative relationship between IL‐1, IL‐17, monocyte chemotactic protein‐3, tumor necrosis factor‐β, and brain iron content in distinct regions. Conclusions Our findings suggest a causal association between circulating inflammatory cytokines and brain iron deposition across various brain regions. This provides new insights into the immunopathogenesis of neurodegenerative diseases and potential preventive strategies targeting iron metabolism.