Causal associations between iron status and sepsis: a Mendelian randomisation analysis

Iron deficiency is associated with a substantial burden of morbidity. However, supplementation of iron has been linked to increased rates of serious infection in randomised trials of children in sub-Saharan Africa. Randomised trials in other settings have been inconclusive and it is unknown if changes in levels of iron biomarkers – a mark of setpoint changes in iron homeostasis - are linked to sepsis in these other settings. We used genetic variants associated with levels of iron biomarkers as instrumental variables in a Mendelian randomisation (MR) analysis to test the hypothesis that increasing levels of iron biomarkers increase the risk of sepsis. In observational and MR analyses we found that increases in iron biomarkers increase the risk of sepsis. In stratified analyses, we show that this risk may be larger in those with iron deficiency and/or anaemia. Taken together, results here suggest a required caution in supplementation of iron and underline the role of iron homeostasis in severe infection. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement FHs time was funded by the GW4-CAT Wellcome Doctoral Fellowship Scheme. UK Biobank was funded by the Wellcome Trust, the Medical Research Council, the NIHR, and a variety of other charities (https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/our-funding). FinnGen is a public-private partnership (https://www.finngen.fi/en/access_results) funded by multiple instititions across Finland. We want to acknowledge the participants and investigators of the FinnGen study. PGs time was funded by the Ser Cymru programme. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank received ethical approval from the Research Ethics Committee (REC reference for UK Biobank is 11/NW/0382). This study was performed under application number 52643. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Access to individual data for UK Biobank is via application to the independent data access committee. For this paper, summary outcome GWAS are available at the OpenGWAS repository (https://gwas.mrcieu.ac.uk/datasets/ieu-b-5066/), and summary exposure data are available at deCODE.genetics website (https://www.decode.com/summarydata/), and therefore MR results can be replicated using the TwoSampleMR package.