Sobczyk and Gaunt genetically predicted circulating zinc, selenium, copper, and vitamin K1 levels—instead of directly measuring nutrients in blood—and hypothesized that these levels would associate with SARS-CoV-2 infection and COVID-19 severity [1]. We have concerns about their conclusions regarding vitamin K in COVID-19. Major study limitations were that the genetic instruments had not demonstrated reliable association with the measured exposure (plasma vitamin K1) and that the authors used the same genome-wide association study for instrument discovery and effect estimation. Moreover, even direct quantification of blood vitamin K1 concentrations is not a valid method for quantifying vitamin K1 status, since this assessment only reflects a snapshot of recent vitamin K1 intake, is sensitive to triglyceride concentrations, and gives little information about the vitamin K1 utilization in tissue.
There are also differences between vitamins K1 and K2 in half-life time, tissue distribution, and bioavailability [2]. Vitamin K2 has a much longer half-life and may, therefore, be important particularly during acute illness, where vitamin K reserves are being used and become less available in peripheral tissues. Consumption of vitamin K2 is usually too low to accurately quantify their plasma concentration. Due to these factors, most experts in the field advocate measuring levels of inactive circulating vitamin-K-dependent proteins to assess the combined deficiency of vitamins K1 and K2. In our studies, we used PIVKA-II and dp-ucMGP as measures of hepatic and extrahepatic vitamin K status, respectively [3,4,5]. Particularly extrahepatic vitamin K status is severely compromised in COVID-19, and high dp-ucMGP levels are associated with increased mortality [4,5].
Another debatable assumption made by Sobczyk and Gaunt is that the baseline vitamin K status—at the moment of SARS-CoV-2 contraction—is a predictive factor for the disease course of subsequently developing COVID-19 [1]. An alternative explanation for the poor vitamin K status in COVID-19 patients is high vitamin K expenditure during the disease. Interestingly, observations in individuals using vitamin K antagonists as anticoagulant drugs support our theory that it is mainly increased vitamin K utilization during the infection, rather than poor baseline vitamin K status, that is responsible for the extrahepatic vitamin K deficiency we found in our studies [6,7].
Given that Sobczyk and Gaunt may not have accurately predicted overall extrahepatic vitamin K status, and that they estimated pre-COVID rather than vitamin K levels during the infection, we are of the opinion that their genetic data analysis is interesting but cannot be used to decide whether vitamin K supplementation has a role in COVID-19.
Author Contributions
Writing—original draft preparation, R.J.; writing—review and editing, C.V., J.W. and A.L. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
R.J. discloses the application of a patent on vitamin K in COVID-19. R.J., J.W., and A.L. have a scientific collaboration with Kappa Bioscience AS, a manufacturer of vitamin K2 (MK-7). C.V. declares no competing interest.
Footnotes
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