key: cord-0967001-tfo8xrkr authors: Alshahawey, Mona title: A genetic insight into vitamin D binding protein and COVID-19 date: 2021-02-09 journal: Med Hypotheses DOI: 10.1016/j.mehy.2021.110531 sha: 9311357ed19c227e0d4595030bf5190d8463f18e doc_id: 967001 cord_uid: tfo8xrkr It’s since December 2019 that Corona virus disease (COVID-19) has emerged to be the global issue of concern. A “pandemic”; this is what WHO has declared about the COVID-19 outbreak on March 3rd, 2020. Vitamin D and its deficiency have recently been claimed to be one of the potential factors affecting COVID-19 risks and outcomes [1]. As Selberstein et al., has recently discussed the effect of vitamin D deficiency, and the role of vitamin D supplementation in COVID-19 patients [2], I’d believe that vitamin D binding protein (DBP) is maybe also involved. A closer look on DBP and its action on regulating the circulatory vitamin D levels, its polymorphisms and their impact on COVID-19 prevalence and mortality, will be briefly discussed. It's since December 2019 that Corona virus disease has emerged to be the global issue of concern. A "pandemic"; this is what WHO has declared about the COVID-19 outbreak on March 3rd, 2020. Vitamin D and its deficiency have recently been claimed to be one of the potential factors affecting COVID-19 risks and outcomes [1] . As Selberstein et al., has recently discussed the effect of vitamin D deficiency, and the role of vitamin D supplementation in COVID-19 patients [2] , I'd believe that vitamin D binding protein (DBP) is maybe also involved. A closer look on DBP and its action on regulating the circulatory vitamin D levels, its polymorphisms and their impact on COVID-19 prevalence and mortality, will be briefly discussed. Vitamin D deficiency is considered as a global pandemic, with more than one billion subjects affected [3] . This deficiency is even more obvious in patients with kidney diseases, lacking the 1hydroxy activating step [4] . However, there is increasing body of evidence supporting the idea of the extra-renal vitamin D metabolism machinery, through extra-renal vitamin D receptors. These receptors are not only regulating the vitamin D circulatory levels [4] , but also seems to play a critical role on its immunomodulatory responses [5] . Recently, vitamin D deficiency was accused to be a risk factor for COVID-19. Vitamin D could act as an inhibitor for the virus entry through interacting with the angiotensin converting enzyme-2 receptor (ACE2), the one that serves as the entry point for the virus which having its (S) protein spike [6] . Calcitriol or (di-hydroxy vitamin D) can exert pronounced effects on ACE2/Angiotensin (1-7)/Mas receptor axis, enhancing the expression of ACE2 [7] . However, ACE2 polymorphisms have also been reported in different populations [6] . Additionally, there are increasing evidences reporting the vitamin D modulatory response on the macrophages, preventing them from the extra release of inflammatory cytokines and chemokines (Cytokine storm) [8] . As there are already published data correlating vitamin D deficiency with severe COVID-19, and illustrating the role of vitamin D in both adaptive and innate immunity, various ongoing studies are also addressing the effect of vitamin D and vitamin D related gene polymorphisms on patients with COVID-19 [9, 10] . Vitamin D binding protein (DBP); which is mainly produced in liver, is regulating vitamin D circulating metabolites (free and total metabolites) [11, 12] . It's worth noting that DBP is not influenced by vitamin D levels, but it's regulated by estrogen, glucocorticoids and inflammatory cytokines. Indeed, DBP is known to be the most polymorphic protein, with it different alleles that are substantially affecting its biologic functions [11] . There are two most common DBP alleles; rs7041 and rs4588, which have been implicated on the pathogenesis of various clinical conditions [11] , mainly by their affinity to vitamin D. Higher plasma levels of 25-hydroxy vitamin D (25(OH)D) were shown to be associated with subjects having the AA genotype within the rs4588 locus. While patients with GG genotype have shown less 25(OH)D levels after same dose of vitamin D supplementation [13] . Interestingly, both allelic variants (rs7041 and rs4588) are also donated to be associated to chronic obstructive pulmonary disease (COPD) [14] . On the other hand, it was also noticed that rs7041 locus was found to be associated with higher susceptibility to hepatitis C viral infection [15] . As DBP gene polymorphisms have been greatly correlated with higher susceptibility of infections, and vitamin D deficiency in different population [16] [17] [18] , they may also have a role in COVID-19. There are different DBP isoforms influencing vitamin D serum concentration and its bioavailability [14] . By combining this information with the discussed role of vitamin D and its impact on the pathogenesis of COVID-19, I'd hypothesize that a more severe reaction against viral infections is modulated by the human immune system, if no necessary concentrations of bioavailable vitamin D presented. A recent study has showed the rs7041 locus to be associated with increased risk of COVID-19 infection and mortality [19] . Therefore, the association of the genetic polymorphisms of DBP and COVID-19 may depend on the modulatory pleiotropic effects of the bioavailable vitamin D levels. However, there's a genome-wide meta-analysis that has illustrated the DBP to have more four SNPs, which are also affecting the concentration of the 25(OH)D levels: rs2282679 (DBP), rs10741657 (near CYP2R1), rs12785878 (near DHCR7), and finally rs6013897 (at CYP24A1) [20] . In conclusion, I'd highlight the need for further genetic analysis regarding the actual role of DBP genetic variations on the bioavailable vitamin D levels. There's also a need for more detailed studies regarding these genetic alleles, and their relation to the severity and mortality of COVID-19 infected patients. The use of both clinical research and genetic analysis may help us decipher the ambiguities of COVID-19 pandemic. COVID-19 and Vitamin D deficiency; the two pandemics. Are they correlated? Vitamin D: A simpler alternative to tocilizumab for trial in COVID-19? 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Clinical Pharmacy Department Ain Shams University, Cairo, Egypt.