In a recent article posted to the medRxiv* preprint server, investigators demonstrated a link between high iron status and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)- and sepsis-linked hospitalizations.
Study: Iron status and the risk of sepsis and severe COVID-19: A two-sample Mendelian randomization study. Image Credit: angellodeco / Shutterstock
Iron is essential for various physiological functions, including metabolism, immune function, and erythropoiesis. Therefore, defects in iron status, such as iron overload or iron deficiency, can have serious health consequences. Furthermore, there are significant sex disparities in iron status aberrations, with women being more at threat of iron deficit.
Numerous recent studies suggest that cellular and systemic iron-regulating pathways play a critical role in safeguarding hosts from infections. Besides, existing reports have shown that iron is vital for most pathogens’ pathogenicity. Interestingly, multiple observational investigations depicted a connection between iron status and the likelihood of sepsis and severe SARS-CoV-2 infection. Nevertheless, reverse causality and residual confounding could skew these results.
Mendelian randomization (MR) research can circumvent these limitations by employing genetic variants correlated with exposures as instrumental parameters. Yet, no investigation has assessed the function of iron profile on the likelihood of SARS-CoV-2 infection in an MR paradigm, and there is a scarcity of experiments evaluating gender variances employing sex-graded MR assessments.
About the study
The goal of the present study was to determine if there was a link between genetically anticipated iron status biological markers and the likelihood of being hospitalized with SARS-CoV-2 infection or sepsis, using data from major genome-wide association studies (GWAS). The team also evaluated sex differences in the relationships between genetically anticipated iron status and the probability of CoV disease 2019 (COVID-19)-related hospitalization using sex-based summary-level information on iron status and SARS-CoV-2 outcomes. They assessed two distinct COVID-19 outcomes: hospitalized SARS-CoV-2 patients compared with non-hospitalized patients and hospitalized SARS-CoV-2 patients compared with controls from the population.
The authors conducted two-sample MR research and used the inverse-variance weighted (IVW) technique to quantify the impact of genetically predicted iron biological markers (transferrin saturation (TSAT), serum iron, ferritin, and total iron-binding capacity (TIBC)) on the chance of sepsis and hospitalization with COVID-19. Further, they did sex-stratified analyses for assessing the COVID-19 outcomes. Sensitivity analysis included weighted mode, weighted median, and MR Egger.
The researchers noted that iron status in populations was hard to assess because none of the biomarkers of iron perfectly reflect it. Moreover, the GWAS that yielded the iron biomarkers data was published in 2021, with 246,139 European ancestry participants. The genetic vulnerability to sepsis was procured from the Integrative Epidemiology Unit (IEU) OpenGWAS, which contained 454,764 controls and 10,154 sepsis cases characterized as explicit sepsis, and summary-level data from the United Kingdom (UK) biobank. The authors used data from release 5 of the COVID-19 Host Genetics Initiative (HGI), an international effort to assist SARS-CoV-2 infections genetics evaluations.
The MR findings suggested that a heightened genetically proxied iron status, as measured by higher TSAT and serum iron levels and lower TIBC levels, was linked to a higher likelihood of sepsis. In participants with genetically anticipated higher titers of serum iron, the authors discovered a greater chance of being hospitalized with SARS-CoV-2 infection than non-hospitalized COVID-19 patients.
One standard deviation hike in genetically projected serum iron was linked with an odds ratio (OR) of 1.14 for the probability of sepsis. The results were confirmed in TSAT and TIBC analyses, although the ferritin estimate was unclear.
Besides, the team discovered a greater risk of COVID-19-linked hospitalization for serum iron, with an OR of 1.29. In addition, sex-stratified analyses revealed an OR of 1.63 for women and 1.21 for males for hospitalization with COVID-19 linked with a high iron load. Nonetheless, to strongly support a variance, the precision of the sex-based findings was very minimal. Further, the sensitivity studies confirmed the main findings and found no evidence of pleiotropy bias.
The investigators hypothesized that individuals with an elevated iron status might be less able to withstand the acute iron influx found in severe infections, making them more susceptible to sepsis and COVID-19-related hospitalization. Additionally, they discovered that iron level influences the likelihood of sepsis and hospitalization with COVID-19, implying that iron status preceding infection interferes with the immune response to an infection.
According to the researchers, no prior literature has assessed the impact of iron profile on the occurrence or outcome of SARS-CoV-2 infection using MR analysis.
To summarize, the present study explored the impacts of iron status on the chance of severe COVID-19 and sepsis using wide-ranging summary data. The study findings point to a link between genetically predicted high iron status and the likelihood of sepsis-related hospitalization and evidence of an elevated risk of SARS-CoV-2-associated hospitalization.
To analyze any sex variations in the correlations, the authors emphasize the significance of a sex-specific summary-level dataset. Higher iron status had a more marked impact on women than men considering COVID-19-linked hospitalization.
Of note, the current results call for more research into the exact association between iron status and severe infections, evaluating the possibility of better management and therapeutic approaches.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Iron status and the risk of sepsis and severe COVID-19: A two-sample Mendelian randomization study; Randi Marie Mohus, Helene Flatby, Kristin V. Liyanarachi, Andrew T. DeWan, Erik Solligård, Jan Kristian Damås, Bjørn Olav Åsvold, Lise T. Gustad, Tormod Rogne. medRxiv preprint 2022, DOI: https://doi.org/10.1101/2022.06.02.22275901, https://www.medrxiv.org/content/10.1101/2022.06.02.22275901v1