The Effect of Circulating Zinc, Selenium, Copper and Vitamin K1 on COVID-19 Outcomes: A Mendelian Randomization Study

  1. Maria K. Sobczyk
  2. Tom R. Gaunt

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Abstract

Background & Aims: Previous results from observational, interventional studies and in vitro experiments suggest that certain micronutrients possess anti-viral and immunomodulatory activities. In particular, it has been hypothesized that zinc, selenium, copper and vitamin K1 have strong potential for prophylaxis and treatment of COVID-19. We aimed to test whether genetically predicted Zn, Se, Cu or vitamin K1 levels have a causal effect on COVID-19 related outcomes, including risk of infection, hospitalization and critical illness. Methods: We employed a two-sample Mendelian Randomization (MR) analysis. Our genetic variants derived from European-ancestry GWAS reflected circulating levels of Zn, Cu, Se in red blood cells as well as Se and vitamin K1 in serum/plasma. For the COVID-19 outcome GWAS, we used infection, hospitalization or critical illness. Our inverse-variance weighted (IVW) MR analysis was complemented by sensitivity analyses including a more liberal selection of variants at a genome-wide sub-significant threshold, MR-Egger and weighted median/mode tests. Results: Circulating micronutrient levels show limited evidence of association with COVID-19 infection, with the odds ratio [OR] ranging from 0.97 (95% CI: 0.87–1.08, p-value = 0.55) for zinc to 1.07 (95% CI: 1.00–1.14, p-value = 0.06)—i.e., no beneficial effect for copper was observed per 1 SD increase in exposure. Similarly minimal evidence was obtained for the hospitalization and critical illness outcomes with OR from 0.98 (95% CI: 0.87–1.09, p-value = 0.66) for vitamin K1 to 1.07 (95% CI: 0.88–1.29, p-value = 0.49) for copper, and from 0.93 (95% CI: 0.72–1.19, p-value = 0.55) for vitamin K1 to 1.21 (95% CI: 0.79–1.86, p-value = 0.39) for zinc, respectively. Conclusions: This study does not provide evidence that supplementation with zinc, selenium, copper or vitamin K1 can prevent SARS-CoV-2 infection, critical illness or hospitalization for COVID-19.

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  1. Version published to 10.3390/nu14020233
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    SciScore for 10.1101/2021.10.18.21265128: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIACUC: Our investigation is in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.
    Sex as a biological variableWe evaluated genetic instruments from the published GWAS of zinc, copper and selenium content of erythrocytes in the Queensland Institute of Medical Research (QIMR) twin cohort and whole blood selenium in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort of pregnant women (61) measured using inductively coupled plasma mass spectrometry.
    RandomizationOur main method was the inverse variance weighted (IVW) random-effects meta-analysis of causal effects of individual instruments as it is the most efficient, however IVW is biased in cases of unbalanced pleiotropy(76).
    Blindingnot detected.
    Power AnalysisThis allowed us to increase statistical power of analysis at the increased risk of violation of core MR assumptions.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    For each micronutrient phenotype, we clumped the instruments using PLINK ver.
    PLINK
    suggested: (PLINK, RRID:SCR_001757)

    Results from OddPub: Thank you for sharing your code and data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    As a caveat, all the real life data and MR analyses do not include application of ionophores which may be necessary for zinc’s antiviral inhibition(14,15). Moreover, a number of observational studies established correlation between low serum selenium levels and COVID-19 severity and mortality(81,84–86). An ecological study found a significant positive association between hair selenium concentration and COVID-19 recovery rate in different provinces of China(87) which was subsequently replicated using local soil selenium concentrations as the predictor variable(88). In general, one way to partially reconcile our findings for selenium and zinc with general micronutrient deficit in hospitalized or severely ill COVID-19 patients found in small studies comes from previous observations in critically ill individuals. There, the initial hypozincemia and hyposelenemia is thought to stem from disease-driven inflammatory process (acute phase response), is found chiefly in plasma (but not e.g. erythrocytes)(13,89,90) and recovers over time in survivors. However, this does not mean that pre-existing deficiencies will not have a compounded negative impact at this stage(50). A recently published study suggested that Cu status is correlated with survival status of COVID-19 patients(32). In contrast, another study from Skalny et al.(86) reported that plasma copper levels and Cu/Zn ratio increased in more severe disease. This could reflect the fact that copper and zinc are antagonistically abso...

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    Results from scite Reference Check: We found no unreliable references.

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  3. Version published to 10.1101/2021.10.18.21265128v1 on medRxiv