ABSTRACT
In their correspondence arising from our recent manuscript [...].
Subject(s)
COVID-19 , Selenium , Copper , Humans , Mendelian Randomization Analysis , Nutrients , SARS-CoV-2 , Vitamin K 1 , ZincABSTRACT
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 [...].
Subject(s)
COVID-19 , Selenium , Copper , Humans , Mendelian Randomization Analysis , Nutrients , SARS-CoV-2 , Vitamin K 1 , ZincABSTRACT
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.
Subject(s)
COVID-19/genetics , Copper/blood , Selenium/blood , Vitamin K 1/blood , Zinc/blood , Adolescent , Adult , Child , Cohort Studies , Female , Genome-Wide Association Study , Hospitalization/statistics & numerical data , Humans , Male , Mendelian Randomization Analysis , Middle Aged , Odds Ratio , Pregnancy , SARS-CoV-2 , White People/genetics , Young AdultABSTRACT
BACKGROUND: Respiratory failure and thromboembolism are frequent in severe acute respiratory syndrome coronavirus 2-infected patients. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease. METHODS: A total of 135 hospitalized COVID-19 patients were compared with 184 historic controls. Inactive vitamin K-dependent MGP (desphospho-uncarboxylated [dp-uc] MGP) and prothrombin (PIVKA-II) were measured inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was measured to quantify the rate of elastic fiber degradation. Arterial calcification severity was assessed using computed tomography. RESULTS: dp-ucMGP was elevated in COVID-19 patients compared with controls (Pâ <â .001), with even higher dp-ucMGP in patients with poor outcomes (Pâ <â .001). PIVKA-II was normal in 82.1% of patients. dp-ucMGP was correlated with desmosine (Pâ <â .001) and with coronary artery (Pâ =â .002) and thoracic aortic (Pâ <â .001) calcification scores. CONCLUSIONS: dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome; hepatic procoagulant factor II remained unaffected. These data suggest pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively.