A genetic insight into vitamin D binding protein and COVID-19

Abstract

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.

To the Editor

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.

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 1-hydroxy 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 bio-availability [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.

Funding

No source of funding or sponsorship.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.