Liver Iron Overload Drives COVID-19 Mortality: a Two-Sample Mendelian Randomization Study

Iron overload has been associated with an increased risk of COVID-19 severity and mortality in observational studies, but it remains unclear whether these associations represent causal effects. We performed a two-sample Mendelian randomization (MR) to determine associations between genetic liability to iron overload and the risk of COVID-19 severity and mortality. From genome-wide association studies of European ancestry, single-nucleotide polymorphisms associated with liver iron (n = 32,858) and ferritin (n = 23,986) were selected as exposure instruments, and summary statistics of the hospitalization (n = 16,551) and mortality (n = 15,815) of COVID-19 were utilized as the outcome. We used the inverse-variance weighted (IVW) method as the primary analysis to estimate causal effects, and other alternative approaches as well as comprehensive sensitivity analysis were conducted for estimating the robustness of identified associations. Genetically predicted high liver iron levels were associated with an increased risk of COVID-19 mortality based on the results of IVW analysis (OR = 1.38, 95% CI: 1.05-1.82, P = 0.02). Likewise, sensitivity analyses showed consistent and robust results in general (all P > 0.05). A higher risk of COVID-19 hospitalization trend was also observed in patients with high liver iron levels without statistical significance. This study suggests that COVID-19 mortality might be partially driven by the iron accumulation in the liver, supporting the classification of iron overload as one of the independent death risk factors. Therefore, avoiding iron overload and maintaining normal iron levels may be a powerful measure to reduce COVID-19 mortality.