Abstract
Background/Aim: Several observational studies showed a significant association between elevated iron status biomarkers levels and sepsis with the unclear direction of causality. A two-sample bidirectional mendelian randomization (MR) study was designed to identify the causal direction between seven iron status traits and sepsis.Methods: Seven iron status traits were studied, including serum iron, ferritin, transferrin saturation, transferrin, hemoglobin, erythrocyte count, and reticulocyte count. MR analysis was first performed to estimate the causal effect of iron status on the risk of sepsis and then performed in the opposite direction. The multiplicative random-effects and fixed-effects inverse-variance weighted, weighted median-based method and MR-Egger were applied. MR-Egger regression, MR pleiotropy residual sum and outlier (MR-PRESSO), and Cochran's Q statistic methods were used to assess heterogeneity and pleiotropy.Results: Genetically predicted high levels of serum iron (OR = 1.21, 95%CI = 1.13–1.29, p = 3.16 × 10−4), ferritin (OR = 1.32, 95%CI = 1.07–1.62, p =0.009) and transferrin saturation (OR = 1.14, 95%CI = 1.06–1.23, p = 5.43 × 10−4) were associated with an increased risk of sepsis. No significant causal relationships between sepsis and other four iron status biomarkers were observed.Conclusions: This present bidirectional MR analysis suggested the causal association of the high iron status with sepsis susceptibility, while the reverse causality hypothesis did not hold. The levels of transferrin, hemoglobin, erythrocytes, and reticulocytes were not significantly associated with sepsis. Further studies will be required to confirm the potential clinical value of such a prevention and treatment strategy.
Highlights
Iron is considered an essential nutrient for both humans and pathogenic microbes
Independent single nucleotide polymorphisms (SNPs) were selected as genetic instrumental variables based on independent and linkage disequilibrium (LD) analyses, including two serum iron-associated SNPs, three independent ferritin-associated
The results showed that the genetically predicted high levels of serum iron (OR = 1.21, 95%CI = 1.13–1.29, p = 3.16 × 10−4), ferritin (OR = 1.32, 95%CI = 1.07–1.62, p = 0.009), and transferrin saturation (OR = 1.14, 95%CI = 1.06–1.23, p = 5.43 × 10−4) were associated with an increased risk of sepsis
Summary
Iron is considered an essential nutrient for both humans and pathogenic microbes. Iron limitation defends pathogenic microbes as a key form of innate immune, termed “nutritional immunity” [1, 2]. Iron overload-associated diseases, such as hereditary hemochromatosis and β-thalassemia, were found increased infection susceptibility [1, 3]. Several MR studies gave evidence of a significant effect of genetically high iron status on the susceptibility of skin and soft tissue infections. Antibiotic therapy was a widely accepted treatment for sepsis, which benefitted patients by improving survival prognosis [6,7,8]. The above references suggest that early intervention is of great significance. The general consensus is that early identification of risk factors is essential for the early intervention of sepsis
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