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

Mohus, Randi Marie; Flatby, Helene M.; Liyanarachi, Kristin Vardheim; DeWan, Andrew T.; Solligård, Erik; Damås, Jan Kristian; Åsvold, Bjørn Olav; Gustad, Lise Tuset; Rogne, Tormod

doi:10.1038/s41598-022-20679-6

Cited by 16 publications

(10 citation statements)

References 58 publications

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“…This may indicate that several of these micronutrients are not important risk factors for the infections considered. Finally, high levels of serum iron have in previous MR studies been associated with skin and soft tissue infections and sepsis, but we did not find any evidence of an association for the infections that we considered [58,59]. This discrepancy may be due to organ-specific effects of iron (e.g., iron levels were also associated with damages to skin-related structures) and that the infectious diseases are not comparable (e.g., sepsis is an inflammatory syndrome in response to severe infection) [59,60].…”

Section: Discussioncontrasting

confidence: 68%

Circulating levels of micronutrients and risk of infections: a Mendelian randomization study

Flatby

Ravi²,

Damås³

et al. 2023

BMC Med

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Background Micronutrients play an essential role at every stage of the immune response, and deficiencies can therefore lead to increased susceptibility to infections. Previous observational studies and randomized controlled trials of micronutrients and infections are limited. We performed Mendelian randomization (MR) analyses to evaluate the effect of blood levels of eight micronutrients (copper, iron, selenium, zinc, beta-carotene, vitamin B12, vitamin C, and vitamin D) on the risk of three infections (gastrointestinal infections, pneumonia, and urinary tract infections). Methods Two-sample MR was conducted using publicly available summary statistics from independent cohorts of European ancestry. For the three infections, we used data from UK Biobank and FinnGen. Inverse variance-weighted MR analyses were performed, together with a range of sensitivity analyses. The threshold for statistical significance was set at P < 2.08E−03. Results We found a significant association between circulating levels of copper and risk of gastrointestinal infections, where a one standard deviation increase in blood levels of copper was associated with an odds ratio of gastrointestinal infections of 0.91 (95% confidence interval 0.87 to 0.97, P = 1.38E−03). This finding was robust in extensive sensitivity analyses. There was no clear association between the other micronutrients and the risk of infection. Conclusions Our results strongly support a role of copper in the susceptibility to gastrointestinal infections.

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Section: Discussioncontrasting

confidence: 68%

Circulating levels of micronutrients and risk of infections: a Mendelian randomization study

Flatby

Ravi²,

Damås³

et al. 2023

BMC Med

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“…The analysis did not show reliable evidence of any plausible significant associations of micronutrients’ status and vulnerability to infection or COVID-19 severity [21 ▪▪ ]. This finding was corroborated for vitamin C [22,23], but not for iron, for which higher genetically predicted status had been associated with sepsis [24].…”

Section: Micronutrients and Coronavirus Disease 2019mentioning

confidence: 82%

Micronutrients, genetics and COVID-19

Kotur

Stanković

Pavlović

2023

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

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Purpose of reviewMarked inter-individual differences in the clinical manifestation of coronavirus disease 2019 (COVID-19) has initiated studies in the field of genetics. This review evaluates recent genetic evidence (predominantly in the last 18 months) related to micronutrients (vitamins and trace elements) and COVID-19.Recent findingsIn patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), altered circulating levels of micronutrients may serve as prognostic markers of disease severity. Mendelian randomization (MR) studies did not find significant effect of variable genetically predicted levels of micronutrients on COVID-19 phenotypes, however, recent clinical studies on COVID-19 point out to vitamin D and zinc supplementation as a nutritional strategy to reduce disease severity and mortality. Recent evidence also points to variants in vitamin D receptor (VDR) gene, most notably rs2228570 (FokI) “f” allele and rs7975232 (ApaI) “aa” genotype as poor prognostic markers.SummarySince several micronutrients were included in the COVID-19 therapy protocols, research in the field of nutrigenetics of micronutrients is in progress. Recent findings from MR studies prioritize genes involved in biological effect, such as the VDR gene, rather than micronutrient status in future research. Emerging evidence on nutrigenetic markers may improve patient stratification and inform nutritional strategies against severe COVID-19.

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“…Our data show a possible connection between the redox imbalance reported in COVID-19 and long-COVID and altered iron metabolism. Interestingly, it has been reported that susceptibility to viral infection with HIV, H1N1, SARS, and COVID-19 is associated with iron levels [129][130][131], and increased plasma levels of free iron correlate with adverse outcomes for COVID-19 patients [132,133]. Previous studies have demonstrated the antiviral effects of iron-chelators, such as deferoxamine (DFO) or deferiprone, for HIV, HSV-1, and CMV [56,57,134,135], and iron chelation therapies are shown to be effective in the management of COVID-19 patients by decreasing the production of free radicals and reducing IL-6 levels [129,136].…”

Section: Discussionmentioning

confidence: 99%

Iron Dyshomeostasis in COVID-19: Biomarkers Reveal a Functional Link to 5-Lipoxygenase Activation

Dufrusine

Valentinuzzi

Bibbò

et al. 2022

IJMS

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Coronavirus disease 2019 (COVID-19) is characterized by a broad spectrum of clinical symptoms. After acute infection, some subjects develop a post-COVID-19 syndrome known as long-COVID. This study aims to recognize the molecular and functional mechanisms that occur in COVID-19 and long-COVID patients and identify useful biomarkers for the management of patients with COVID-19 and long-COVID. Here, we profiled the response to COVID-19 by performing a proteomic analysis of lymphocytes isolated from patients. We identified significant changes in proteins involved in iron metabolism using different biochemical analyses, considering ceruloplasmin (Cp), transferrin (Tf), hemopexin (HPX), lipocalin 2 (LCN2), and superoxide dismutase 1 (SOD1). Moreover, our results show an activation of 5-lipoxygenase (5-LOX) in COVID-19 and in long-COVID possibly through an iron-dependent post-translational mechanism. Furthermore, this work defines leukotriene B4 (LTB4) and lipocalin 2 (LCN2) as possible markers of COVID-19 and long-COVID and suggests novel opportunities for prevention and treatment.

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

Cited by 16 publications

References 58 publications

Circulating levels of micronutrients and risk of infections: a Mendelian randomization study

Circulating levels of micronutrients and risk of infections: a Mendelian randomization study

Micronutrients, genetics and COVID-19

Iron Dyshomeostasis in COVID-19: Biomarkers Reveal a Functional Link to 5-Lipoxygenase Activation

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