CoChat
Sign Up
PreprintCited by 28Iron Metabolism and DisordersGenetic Associations and EpidemiologySepsis Diagnosis and Treatment

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

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

Open access
Mohus, Randi Marie, Flatby, Helene, Liyanarachi, Kristin V., DeWan, Andrew T., Solligård, Erik, Damås, Jan Kristian, Åsvold, Bjørn Olav, Gustad, Lise T., Rogne, Tormod·2022·Scientific Reports
DOI 10.1101/2022.06.02.22275901PMC PMC9516524

Preprint — published as 10.1038/s41598-022-20679-6 · Paper page

Open this paper in CoChat — free accountOpen PDF

Abstract

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1101/2022.06.02.22275901

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 47

  1. 2001, Iron biology in immune function, muscle metabolism and neuronal functioning, J Nutr, 131, 568S
  2. 10.1007/s10096-013-1877-x · DOI
  3. 10.1007/s00134-018-5320-8 · DOI
  4. 2020, Linkage of alterations in systemic iron homeostasis to patients’ outcome in sepsis: a prospective study, J Intensive Care, 8, 76, 10.1186/s40560-020-00495-8 · DOI
  5. 2020, Serum trace element and heavy metal levels in patients with sepsis, Aging Male, 23, 222, 10.1080/13685538.2020.1740200 · DOI
  6. 2018, High Serum Iron level is Associated with Increased Mortality in Patients with Sepsis, Scientific Reports, 8, 11072, 10.1038/s41598-018-29353-2 · DOI
  7. 2018, Iron deficiency and infection: another pathway to explore in critically ill patients?, Intensive Care Medicine, 44, 2260, 10.1007/s00134-018-5438-8 · DOI
  8. 2012, Hepcidin and the Iron-Infection Axis, Science (New York, NY), 338, 768, 10.1126/science.1224577 · DOI · Paper page
  9. 2021, Association between iron status and the risk of adverse outcomes in COVID-19, Clin Nutr, 40, 3462, 10.1016/j.clnu.2020.11.033 · DOI
  10. Hippchen T , Altamura S , Muckenthaler MU , Merle U. Hypoferremia predicts hospitalization and oxygen demand in COVID-19 patients. medRxiv. 2020:2020.06.26.20140525. · DOI
  11. 10.1007/s12026-020-09145-5 · DOI
  12. 2021, The U-shaped association of serum iron level with disease severity in adult hospitalized patients with COVID-19, Scientific Reports, 11, 13431, 10.1038/s41598-021-92921-6 · DOI · Paper page
  13. Galmés S , Serra F , Palou A. Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework. Nutrients. 2020;12(9). · DOI
  14. 2022, Explaining sex differences in risk of bloodstream infections using mediation analysis in the population-based HUNT study in Norway, Sci Rep, 12, 8436, 10.1038/s41598-022-12569-8 · DOI
  15. 2021, Sex-based differences in severity and mortality in COVID-19, Reviews in Medical Virology, 31, e2223, 10.1002/rmv.2223 · DOI
  16. 2020, Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission, Nature Communications, 11, 6317, 10.1038/s41467-020-19741-6 · DOI · Paper page
  17. 10.1136/bmj.k601 · DOI · Paper page
  18. 2021, Causal Effects of Genetically Predicted Iron Status on Sepsis: A Two-Sample Bidirectional Mendelian Randomization Study, Front Nutr, 8, 747547, 10.3389/fnut.2021.747547 · DOI
  19. 2021, A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis, Commun Biol, 4, 156, 10.1038/s42003-020-01575-z · DOI
  20. 10.1016/S0140-6736(20)31561-0 · DOI · Paper page
  21. 10.1093/ije/dyr036 · DOI · Paper page
  22. Hemani G , Zheng J , Elsworth B , Wade KH , Haberland V , Baird D , et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018;7. · DOI · Paper page
  23. 2020, MendelianRandomization v0.5.0: updates to an R package for performing Mendelian randomization analyses using summarized data, Wellcome Open Res, 5, 252, 10.12688/wellcomeopenres.16374.2 · DOI
  24. 10.1016/S0140-6736(19)32989-7 · DOI · Paper page
  25. Elsworth B , Lyon M , Alexander T , Liu Y , Matthews P , Hallett J , et al. The MRC IEU OpenGWAS data infrastructure. bioRxiv. 2020:2020.08.10.244293. · DOI
  26. Mapping the human genetic architecture of COVID-19, 2021, Nature, 600, 472, 10.1038/s41586-021-03767-x · DOI
  27. 10.1093/bioinformatics/btu273 · DOI
  28. 2019, Guidelines for performing Mendelian randomization investigations, Wellcome Open Res, 4, 186, 10.12688/wellcomeopenres.15555.1 · DOI
  29. 10.1002/gepi.21965 · DOI · Paper page
  30. 10.1093/ije/dyx102 · DOI · Paper page
  31. 10.1093/ije/dyv080 · DOI · Paper page
  32. 2019, PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations, Bioinformatics, 35, 4851, 10.1093/bioinformatics/btz469 · DOI
  33. 10.1136/bmj.n2233 · DOI · Paper page
  34. 10.1097/EDE.0000000000000161 · DOI
  35. 10.1038/ncomms5926 · DOI · Paper page
  36. 10.1371/journal.pmed.1002833 · DOI · Paper page
  37. Bastin A , Shiri H , Zanganeh S , Fooladi S , Momeni Moghaddam MA , Mehrabani M , et al. Iron Chelator or Iron Supplement Consumption in COVID-19? The Role of Iron with Severity Infection. Biol Trace Elem Res. 2021:1–11. · DOI
  38. 2020, COVID-19 gone bad: A new character in the spectrum of the hyperferritinemic syndrome?, Autoimmun Rev, 19, 102573, 10.1016/j.autrev.2020.102573 · DOI
  39. 10.1056/NEJMra041809 · DOI · Paper page
  40. 10.1016/S0140-6736(06)67962-2 · DOI · Paper page
  41. 2021, The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators, Biomedicine & Pharmacotherapy, 136, 111228, 10.1016/j.biopha.2021.111228 · DOI
  42. 2022, Therapeutic potential of induced iron depletion using iron chelators in Covid-19, Saudi Journal of Biological Sciences, 29, 1947, 10.1016/j.sjbs.2021.11.061 · DOI
  43. 2021, Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis, Life (Basel), 11, 57
  44. Campione E , Lanna C , Cosio T , Rosa L , Conte MP , Iacovelli F , et al. Lactoferrin as potential supplementary nutraceutical agent in COVID-19 patients: in vitro and in vivo preliminary evidences. bioRxiv. 2020:2020.08.11.244996. · DOI
  45. 2020, A comparison of robust Mendelian randomization methods using summary data, Genet Epidemiol, 44, 313, 10.1002/gepi.22295 · DOI
  46. 2019, Heterogeneity in sepsis: new biological evidence with clinical applications, Critical care (London, England), 23, 80, 10.1186/s13054-019-2372-2 · DOI
  47. 10.1093/aje/kwy204 · DOI · Paper page

Metadata

Authors
Mohus, R. M., Flatby, H., Liyanarachi, K. V., DeWan, A. T., Solligård, E., Damås, J. K., Åsvold, B. O., Gustad, L. T., & Rogne, T.
Affiliations
  • Norwegian University of Science and Technology (NO)
  • Norwegian Institute of Public Health (NO)
Corresponding author
Mohus, Randi Marie
ORCID
Venue
Scientific Reports
Publisher
openRxiv
Published
2022-06-02
Volume
12
Issue
1
Pages
16157-16157
ISSN
2045-2322 (ISSN-L)
DOI
10.1101/2022.06.02.22275901
PMC
PMC9516524
OpenAlex
W4297473991
Cited by
28
References
1
Citations by year
2026: 3 · 2025: 7 · 2024: 8 · 2023: 9 · 2022: 1
FWCI
4.55
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • medRxiv (acceptedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • NORA - Norwegian Open Research Archives (submittedVersion, other-oa)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
Funders
Norges Teknisk-Naturvitenskapelige Universitet
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Sepsis Diagnosis and Treatment
Keywords
iron status, sepsis, COVID-19 pandemic, serum iron, transferrin saturation, total iron binding capacity, ferritin, hospitalization risk, sex differences, genetic biomarkers, causal effects
MeSH terms
COVID-19, Female, Ferritins, Humans, Iron, Male, Transferrin, Biomarkers, Sepsis, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Mendelian Randomization Analysis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review