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

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.

Cardiometabolic traits, sepsis and severe covid-19 with respiratory failure: a Mendelian randomization investigation (preprint)

ObjectivesTo investigate whether there is a causal effect of cardiometabolic traits on risk of sepsis and severe covid-19. DesignMendelian randomisation analysis. SettingUK Biobank and HUNT study population-based cohorts for risk of sepsis, and genome-wide association study summary data for risk of severe covid-19 with respiratory failure. Participants12,455 sepsis cases (519,885 controls) and 1,610 severe covid-19 with respiratory failure cases (2,205 controls). ExposureGenetic variants that proxy body mass index (BMI), lipid traits, systolic blood pressure, lifetime smoking score, and type 2 diabetes liability - derived from studies considering between 188,577 to 898,130 participants. Main outcome measuresRisk of sepsis and severe covid-19 with respiratory failure. ResultsHigher genetically proxied BMI and lifetime smoking score were associated with increased risk of sepsis in both UK Biobank (BMI: odds ratio 1.38 per standard deviation increase, 95% confidence interval [CI] 1.27 to 1.51; smoking: odds ratio 2.81 per standard deviation increase, 95% CI 2.09-3.79) and HUNT (BMI: 1.41, 95% CI 1.18 to 1.69; smoking: 1.93, 95% CI 1.02-3.64). Higher genetically proxied BMI and lifetime smoking score were also associated with increased risk of severe covid-19, although with wider confidence intervals (BMI: 1.75, 95% CI 1.20 to 2.57; smoking: 3.94, 95% CI 1.13 to 13.75). There was limited evidence to support associations of genetically proxied lipid traits, systolic blood pressure or type 2 diabetes liability with risk of sepsis or severe covid-19. Similar findings were generally obtained when using Mendelian randomization methods that are more robust to the inclusion of pleiotropic variants, although the precision of estimates was reduced. ConclusionsOur findings support a causal effect of elevated BMI and smoking on risk of sepsis and severe covid-19. Clinical and public health interventions targeting obesity and smoking are likely to reduce sepsis and covid-19 related morbidity, along with the plethora of other health-related outcomes that these traits adversely affect. Summary boxesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LISepsis and severe covid-19 are major contributors to global morbidity and mortality. C_LIO_LICardiometabolic risk factors have been associated with risk of sepsis and severe covid-19, but it is unclear if they are having causal effects. C_LI What this study addsO_LIUsing Mendelian randomization analyses, this study provides evidence to support that higher body mass index and lifetime smoking score both increase risk of sepsis and severe covid-19 with respiratory failure. C_LIO_LIClinical and public health interventions targeting obesity and smoking are likely to reduce sepsis and covid-19 related morbidity, along with the plethora of other health-related outcomes that these traits adversely affect. C_LI