Genetic Susceptibility to Causal Relationship Between Iron Metabolism Disorder Involving Immunocytes and Risk of Pneumonia and Sepsis.

Recent studies showed ferritin increase and hemoglobin decrease to COVID-19 severity and sepsis mortality. However, the potential relationship between iron metabolism disorders and susceptibility to pneumonia remains unclear. This study explores the association between iron metabolism disorder and susceptibility to bacterial pneumonia, viral pneumonia, and sepsis. GWAS data from the FinnGen and UK biobank is used for a two-sample Mendelian randomization (MR) analysis, followed by MR meta-analysis. Low serum iron levels were negatively associated with the risk of bacterial pneumonia (OR, 0.85;  = 0.04), influenza pneumonia (OR, 0.86;  = 0.03), and sepsis (OR, 0.81;  = 0.0004). Increased transferrin saturation and decreased total iron-binding capacity were linked to higher risks of bacterial pneumonia and sepsis. Elevated liver iron content correlated positively with susceptibility to bacterial pneumonia (OR, 1.11;  = 0.007), influenza pneumonia (OR, 1.08;  = 0.03), and sepsis (OR, 1.13;  = 0.0007), but negatively with pneumococcal pneumonia (OR, 37.62;  = 0.0013). Neutrophils mediated the impact of serum iron and transferrin saturation on susceptibility to bacterial pneumonia and sepsis. This MR study confirms that disruptions in iron metabolism, including low serum iron levels and elevated liver iron content, increase susceptibility to bacterial and viral pneumonia as well as sepsis by affecting neutrophil function and cytokine levels. The findings emphasize the need for monitoring iron metabolism indicators in high-risk populations and provide valuable insights for further mechanistic research and clinical intervention.