Causal Effects of Genetically Predicted Iron Status on Sepsis: A Two-Sample Bidirectional Mendelian Randomization Study

Hu, Yuanlong; Cheng, Xueyu; Mao, Huaiyu; Chen, Xianhai; Cui, Yue; Qiu, Zhanjun

doi:10.3389/fnut.2021.747547

Cited by 10 publications

(11 citation statements)

References 49 publications

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“…Few MR studies have explored iron status and risk of severe infections. An MR-study using iron related SNPs identified in the Genetics of Iron Status-consortia 45 found evidence that higher serum-iron, TSAT and ferritin were related to increased risk of sepsis 23 . Using a more updated set of genetic instruments for iron status biomarkers, we replicated these findings for serum iron and TSAT, a tendency for TIBC, but not for ferritin.…”

Section: Discussionmentioning

confidence: 99%

“…that the disease affects levels of the exposure) is greatly reduced 22 . A recent MR study found a positive association between genetically-predicted high levels of iron biomarkers and risk of sepsis 23 , but a more recent set of genetic instruments for iron status has since been published 24 . No study has evaluated the role of iron status on the risk of COVID-19 in an MR framework and there is a lack of studies assessing sex differences 25 using sex-stratified MR analyses.…”

Section: Introductionmentioning

confidence: 99%

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

Mohus

Flatby

Liyanarachi

et al. 2022

Sci Rep

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Observational studies have indicated an association between iron status and risk of sepsis and COVID-19. We estimated the effect of genetically-predicted iron biomarkers on risk of sepsis and risk of being hospitalized with COVID-19, performing a two-sample Mendelian randomization study. 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] 1.01–1.29, 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), whereas 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. 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Mohus

Flatby

Liyanarachi

et al. 2022

Sci Rep

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show abstract

“…Few MR studies have explored iron status and risk of severe infections. An MR-study using iron related SNPs identified in the Genetics of Iron Status-consortia (38) found evidence that higher serum-iron, TSAT and ferritin were related to increased risk of sepsis (21). Using a more updated set of genetic instruments for iron status biomarkers, we replicated these findings for serum iron and TSAT, a tendency for TIBC, but not for ferritin.…”

Section: Discussionmentioning

confidence: 99%

“…that the disease affects levels of the exposure) is greatly reduced (20). A recent MR study found a positive association between genetically-predicted high levels of iron biomarkers and risk of sepsis (21), but a more recent set of genetic instruments for iron status has since been published (22). No study has evaluated the role of iron status on the risk of COVID-19 in an MR framework and there is a lack of studies assessing sex differences (23) using sex-stratified MR analyses.…”

Section: Introductionmentioning

confidence: 99%

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

Mohus

Flatby

Liyanarachi

et al. 2022

Preprint

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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.

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“…For instance, the relatively complex pattern of association, identified in other biomarkers (e.g. lymphocyte count, BMI 26,27 ), with increased odds of incident sepsis cases in those with severe iron deficiency likely represents the increased risk associated with the disease driving severe iron deficiency (e.g. malignancy).…”

Section: Strengths and Weaknessesmentioning

confidence: 99%

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

Hamilton

Mitchell

Ahmed

et al. 2022

Preprint

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ObjectiveTo evaluate the association between four iron biomarkers and sepsis.DesignAn observational cohort and two sample Mendelian randomisation (MR) study.SettingThe UK Biobank prospective cohort study (for the observational cohort and for MR outcomes), the FinnGEN cohort study (replication of MR outcomes) and three large genome wide association studies (GWAS, for iron exposures).Participants453,169 participants enrolled in UK Biobank, 356,000 participants enrolled in FinnGen and between 131,471 - 246,139 participants enrolled across the three iron biomarker GWAS.ExposuresIn the observational cohort, iron status was determined using ferritin levels recorded in general practice data. In the MR analyses, four iron biomarkers were used: serum iron, serum ferritin, the total iron binding capacity (TIBC), and transferrin saturation (TSAT).Main outcome measuresHospital admission with an ICD-10 coded sepsis diagnosis.ResultsIn the observational cohort, the odds of sepsis increased as ferritin levels increased, with odds ratios of >1 once ferritin was more than >160 ug/L, within the normal accepted reference range for ferritin. Extremely low ferritin (<40ug/L) was also associated with increased odds of sepsis.In inverse-variance-weighted mendelian randomisation analyses, increases in all iron biomarkers were associated with increasing odds of sepsis (OR 1.10 for each SD increase in TSAT; 95% CI 1.03 to 1.17) with similar results for serum iron (OR 1.07; 95% CI 0.98 to 1.16), and ferritin (OR 1.09; 95% CI 0.99 to 1.2), with the opposite result for TIBC (OR 0.92; 95% CI 0.86 to 0.99). Effect estimates were slightly larger in those with iron deficiency or anaemia.Results were similar in the replication cohort (FinnGen) and were robust to sensitivity analyses of Mendelian randomisation.ConclusionsIncreasing measures of iron and related biomarkers are associated with increased risk of sepsis in a healthy adult volunteer cohort. MR analyses suggest this association is causal. Clinicians and policymakers should be aware of this potential risk when manipulating iron levels.

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Causal Effects of Genetically Predicted Iron Status on Sepsis: A Two-Sample Bidirectional Mendelian Randomization Study

Cited by 10 publications

References 49 publications

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

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

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

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

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