Iron status and the risk of sepsis and severe COVID-19: A two-sample Mendelian randomization study

Introduction Observational studies have indicated an association between iron status and risk of sepsis and severe COVID-19. However, these findings may be affected by residual confounding, reverse causation. Methods In a two-sample Mendelian randomization study using inverse variance weighted method, we estimated the effect of genetically-predicted iron biomarkers (serum iron, transferrin saturation (TSAT), total iron binding capacity (TIBC) and ferritin) on risk of sepsis and risk of being hospitalized with COVID-19. For the COVID-19 outcomes we additionally conducted sex-stratified analyses. Weighted median, Weighted mode and MR Egger were used as sensitivity analyses. Results For risk of sepsis, one standard deviation increase in genetically-predicted serum iron was associated with odds ratio (OR) of 1.14 (95% confidence interval [CI] 1.01 to 1.29, P =0.031). The findings were supported in the analyses for transferrin saturation and total iron binding capacity, while the estimate for ferritin was inconclusive. We found a tendency of higher risk of hospitalization with COVID-19 for serum iron; OR 1.29 (CI 0.97–1.72, P =0.08), where sex stratified analyses showed OR 1.63 (CI 0.94–2.86, P =0.09) for women and OR 1.21 (CI 0.92–1.62, P =0.17) for men. Sensitivity analyses supported the main findings and did not suggest bias due to pleiotropy. Conclusions Our findings suggest a causal effect of genetically-predicted higher iron status and risk of hospitalization due to sepsis and indications of an increased risk of being hospitalized with COVID-19. These findings warrant further studies to assess iron status in relation to severe infections, including the potential of improved management.