key: cord-0899068-qhwceimv authors: Jain, Sushil K.; Parsanathan, Rajesh; Levine, Steve N.; Bocchini, Joseph A.; Holick, Michael F.; Vanchiere, John A. title: The potential link between inherited G6PD deficiency, oxidative stress, and vitamin D deficiency and the racial inequities in mortality associated with COVID-19() date: 2020-10-07 journal: Free Radic Biol Med DOI: 10.1016/j.freeradbiomed.2020.10.002 sha: bdb12b675dbfa31bc96f5b91c4ca008996aa9ee1 doc_id: 899068 cord_uid: qhwceimv There is a marked variation in mortality risk associated with COVID-19 infection in the general population. Low socioeconomic status and other social determinants have been discussed as possible causes for the higher burden in African American communities compared with white communities. Beyond the social determinants, the biochemical mechanism that predisposes individual subjects or communities to the development of excess and serious complications associated with COVID-19 infection is not clear. Virus infection triggers massive ROS production and oxidative damage. Glutathione (GSH) is essential and protects the body from the harmful effects of oxidative damage from excess reactive oxygen radicals. GSH is also required to maintain the VD-metabolism genes and circulating levels of 25-hydroxyvitamin D (25(OH)VD). Glucose-6-phosphate dehydrogenase (G6PD) is necessary to prevent the exhaustion and depletion of cellular GSH. X-linked genetic G6PD deficiency is common in the AA population and predominantly in males. Acquired deficiency of G6PD has been widely reported in subjects with conditions of obesity and diabetes. This suggests that individuals with G6PD deficiency are vulnerable to excess oxidative stress and at a higher risk for inadequacy or deficiency of 25(OH)VD, leaving the body unable to protect its ‘oxidative immune-metabolic’ physiological functions from the insults of COVID-19. An association between subclinical interstitial lung disease with 25(OH)VD deficiencies and GSH deficiencies has been previously reported. We hypothesize that the overproduction of ROS and excess oxidative damage is responsible for the impaired immunity, secretion of the cytokine storm, and onset of pulmonary dysfunction in response to the COVID-19 infection. The co-optimization of impaired glutathione redox status and excess 25(OH)VD deficiencies has the potential to reduce oxidative stress, boost immunity, and reduce the adverse clinical effects of COVID-19 infection in the AA population. cough, shortness of breath, and difficulty breathing. These symptoms are reported to range from mild 63 to severe. While symptoms may appear 2-14 days after exposure to the virus, some people infected 64 with COVID-19 do not display any symptoms-the clinical symptoms and mortality associated with 65 COVID-19 show racial and ethnic disparities. The rates of hospitalization and severity associated with 66 COVID-19 are highest in the AA males [1, 2] . Previous reports suggest that AA are more likely to be 67 exposed to COVID-19 due to social determinants, such as low socioeconomic status, employment in 68 jobs considered essential during the pandemic, and a greater reliance on public transportation, all of 69 which lead to greater potential exposure. In addition, a disproportionately higher percentage of AA has 70 underlying health conditions, such as diabetes and hypertension. The incidence and severity of 71 infection associated with COVID-19 and G6PD deficiency are higher in males, and both are higher in 72 The reasons why AA have died from the disease at almost three times the rate of whites and 74 have a disproportionately higher rate of severe complications as a result of the coronavirus pandemic 75 is not understood. This paper reviews the literature and discusses the mechanistic evidence-based 76 hypothesis for an interdependent link between G6PD and 25(OH)VD deficiencies with the COVID-19 77 associated higher risk in the AA population. The molecular mechanisms underlie the potential role of 78 the inherited genotypes and co-morbidity-associated phenotypes combined with viral infection-79 mediated excess oxidative stress in the disproportionately higher mortality rate in AA. The activation of a macrophage respiratory burst in response to infection with COVID-19 can induce 87 the onset of ROS production and inflict oxidative damage to the host's tissues. ROS ventricular dilation in response to myocardial infarction or pressure overload-induced heart failure. 138 G6PD-deficient heart tissue, which does not recover and healthy heart tissue from ischemia-139 reperfusion injury, is susceptible to cardiac hypertrophy. The adverse effects of G6PD deficiency may 140 outweigh the potential protective effects of G6PD, particularly in the case of cardiac stress [32] . In vitro and in vivo infusion of aldosterone decreases vascular G6PD expression and impairs vascular 162 reactivity [44] . Aldosterone increases oxidative stress, decreases G6PD activity, and impairs vascular 163 reactivity [44] . Aldosterone induces a G6PD-deficient phenotype, impairs endothelial function; gene 164 J o u r n a l P r e -p r o o f transfer of G6PD improves vascular reactivity by restringing G6PD [44] . Thus, excess psychological 165 stress and increased aldosterone levels can further lower the G6PD activity in those with the genetic 166 G6PD variant phenotype. Hyperglycemia levels and diabetes are independent predictors of mortality 167 and morbidity in patients with SARS-CoV-2 infection [45, 46] . Hyperglycemia, diabetes, oxidative 168 stress favors glycosylation of proteins, which can further diminishes G6PD activity and its protective 169 mechanisms particularly in those who has inherited G6PD-deciency [47] [48] [49] . In addition, a recent 170 study shows that high induces von Hippel-Lindau (VHL) protein, an E3 ubiquitin ligase subunit, [53]. Glucose-6-phosphate dehydrogenase (G6PD) catalyzes the production of nicotinamide adenine 187 dinucleotide phosphate reduced form (NADPH). Glutathione reductase requires NADPH to recycle 188 oxidized glutathione (GSSG) to GSH. Lower GSH levels can occur because LC is not available in the 189 food consumed, or it can result from the consumption of an energy-rich diet, which increases ROS 190 and oxidative stress. GSH depletion increases oxidative stress and extensive carbonylation of 191 proteins and modifies endogenous enzymes and proteins, resulting in impaired cellular function [56] . 192 [56] [57] [58] . In vitro studies showed that partial depletion of the intracellular GSH pool could negatively 205 impair T cells' immune regulatory potential [65] . The intracellular glutathione redox status is also 206 linked to the production of proinflammatory cytokines, such as IFN and IL-4, which regulate IL-12 and 207 T-cell differentiation [66] . GSH or its precursor L-cysteine has been used to replenish intracellular 208 GSH levels in antiviral therapy. Deficiency of G6PD or GSH has been implicated in increasing the 209 inflammation and respiratory distress common to various diseases, such as diabetes, chronic Animal studies have shown that low levels of GSH downregulate the VD-regulatory 220 (VDBP/VD-25-hydroxylase/VDR) and glucose-metabolism (PGC-1α/VDR/GLUT-4) genes in the liver, 221 kidney, and muscle of HFD-fed mice and diabetic rats [56, 58, 73, 81] . Co-supplementation with VD 222 and L-cysteine (a GSH precursor) had significant positive results on increasing GSH compared with 223 supplementation with VD alone in ZDF rats and a mouse model of 25(OH)VD deficiency [56, 73] . 224 These included upregulated VD-regulatory genes in the liver and glucose-metabolism genes in 225 muscle, increased levels of 25(OH)VD, reduced lipid peroxidation, and lower levels of protein carbonyl 226 and TNF in the blood [56] . 227 Cell culture studies showed that GSH deficiency induced in vitro caused increased oxidative 228 stress, downregulation of VDBP/VD-25-hydroxylase/VDR, upregulation of CYP24A1 in hepatocytes, 229 and downregulation of PGC-1α/VDR/GLUT-4 in myotubes [56] . We recently showed that GSH 230 deficiency epigenetically alters VD-biosynthesis pathway genes in HFD-fed obese mice. [2] C.W. Yancy, COVID-19 and African Americans, Jama (2020). 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G6PD deficiency causes NADPH depletion, 689leading to decreased glutathione (GSH) recycling, which induces reactive oxygen species (ROS). 690Excess oxidative stress may favor viral infection, replication, and inflammation. Conversely, viral 691infections, replications, and inflammation are more frequently inhibited by antioxidants (GSH or its 692 precursors, such as N-acetyl cysteine and L-cysteine). 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734