Vitamin D binding protein polymorphism and COVID‐19

Abstract

With interest, we read the paper of Batur et al.,1 which investigated the influence of the vitamin D binding protein (DBP) gene polymorphisms on the prevalence and mortality rate of coronavirus disease 2019 (COVID-19). The GT genotype at rs7041 showed a positive correlation with prevalence and mortality rates of COVID-19, whereas a negative correlation was observed with the TT genotype. No significant correlation was found between the prevalence and mortality data, and the polymorphism at the rs4588 locus. The authors concluded that the difference in susceptibility for and mortality due to COVID-19 among the selected countries might be explained by the presence of vitamin D deficiency due to a different vitamin D metabolism, orchestrated by the DBP polymorphisms of rs7041 and rs4588. However, previous research in healthy, white, premenopausal women showed that the less frequent TT genotype was associated with lower plasma 25-hydroxyvitamin D concentrations in comparison with the more prevalent GG and GT genotypes.2 Besides, the study of Batur et al. included data of only 10 countries. Human DBP is a highly polymorphic protein with three major circulating DBP alleles, which are defined by the genetic polymorphisms rs7041 and rs4588: DBP1F [rs7041-T (ASP), rs4588-C (Thr)], DBP1S [rs7041-G (ASP), rs4588-C (Thr)], and DBP2 [rs7041-T (ASP), rs4588-A (Lys)].3 The DBP1 allele (DBP1F and DBP1S) encodes an anodal and a cathodal band: DBP1a [pI 4.84 (DBP1F), pI 4.85 (DBP1S)] and DBP1c [pI 4.94 (DBP1F), pI 4.95 (DBP1S)]. DBP1F proteins show a faster migration rate in comparison with DBP1S. The posttranslational difference between the DBP1a and DBP1c isoforms is explained by a single N-acetyl-neuraminic acid residue in DBP1a, which is absent in DBP1c. The DBP2 allele encodes one single band (pI 5.1).4 Subjects with white skin have a relatively lower frequency of the DBP1F allele and a higher frequency (50%–60%) of the DBP1S allele. In comparison with populations of African ancestry, which have a high DBP1F allele frequency, a markedly higher DBP2 allele frequency is observed in Caucasians.5 The median plasma concentration of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D is partly determined by the DBP phenotype.6 The potential role of vitamin D and vitamin D-related genes polymorphisms in the prevention and treatment of patients with a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is currently the topic of several studies and ongoing trials.7, 8 Although only limited data about vitamin D status and COVID-19 are available, a higher prevalence of vitamin D deficiency in patients with severe COVID-19 has been published.9, 10 Multiple mechanisms have been proposed to support the hypothesis that vitamin D deficiency is a risk factor for the disease and/or its adverse outcome.10 Besides the systemic synthesis of vitamin D, there is increasing evidence that local, extra-renal vitamin D metabolism may be critical for its immunomodulatory effects. The induction of nonspecific responses could strengthen the role of vitamin D as an inhibitor of virus entry by interacting with the angiotensin-converting enzyme-2 (ACE2) receptor, which serves as the entry point for SARS-CoV-2. Although not yet proven, vitamin D could also potentially modulate the virus replication via interaction with both host cell and virus factors: for example, inhibition of endoplasmic reticulum stress. Furthermore, vitamin D could improve the efficacy of the host response impact by influencing both innate and adaptive immune responses (natural killer cells and T lymphocytes). Finally, vitamin D might also play a key role in the uncontrolled cytokine storm through inhibition of inflammatory responses, increasing ACE2 expression, decreasing the neutrophil to lymphocyte ratio, and inhibition of complement.8 In contrast to the study of Batur et al.,1 which explored the influence of the DBP genotypes, we wanted to investigate the influence of the DBP phenotypes in patients with a SARS-CoV-2 infection. We compared the frequency of the DBP1 allele [a mixture of DBP1F (fast) and DBP1S (slow)] in 55 countries (Table 1) with the prevalence and mortality data of COVID-19, taking into account the time interval since the start of the infection in each country. European, African, Mediterranean, Middle East, and Asian countries were included: Albania, Algeria, Austria, Belarus, Belgium, Bosnia, Bulgaria, China, Congo, Cyprus, Denmark, Djibouti, Germany, Egypt, Estonia, Ethiopia, Finland, France, Greece, Hungaria, Ireland, Iceland, India, Iran, Israel, Italy, Japan, Jordan, Kazachstan, Korea, Croatia, Latvia, Lithuania, Luxemburg, Moldova, Morocco, the Netherlands, Norway, Oman, Poland, Portugal, Romania, Russia, Saudi Arabia, Serbia, Slovenia, Slovakia, Spain, Taiwan, Czech Republic, Tunisia, Turkey, UK, Sweden, and Switzerland. Data reported on July 2, 2020 (same date as used by the authors of the original study) by Johns Hopkins were analyzed. The time interval since the start of the infection in each country was recorded to synchronize the data. In a univariate model, the correlation between COVID-19 prevalence and the DBP1 allele frequency was significant: log (prevalence; no. of cases/106 inhabitants) = 15.64 − 7.22 (DBP1 allele frequency, %) + 0.54 (date of the first case, days since January 1, 2020), r² = 0.116; p = .04. Similarly, the DBP1 allele frequency correlated negatively with COVID-19 mortality: log (mortality; no. of cases/106 inhabitants) = 20.91–10.24 (DBP1 allele frequency, %);− 0.11 (date of first case, days since January 1, 2020), r² = 0.156; p = .01. The association between the DBP1 allele frequency and a lower prevalence and mortality due to a SARS-CoV-2 infection could be partly explained by the potential protective effects of vitamin D, as already described in the paper of Batur et al.1 In a study with healthy, white, premenopausal women, the median plasma concentration of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were highest in DBP 1-1 subjects, intermediate in DBP 2-1 individuals, and lowest in the DBP 2-2 group.11 However, rs7041 and rs4588 explain only 9.9% of the 25-hydroxyvitamin D concentrations. A genome-wide meta-analysis has identified four additional SNPs, which affect the concentration of 25-hydroxyvitamin D: rs2282679 (DBP), rs10741657 (near CYP2R1), rs12785878 (near DHCR7), and rs6013897 (at CYP24A1).12 In conclusion, DBP1 carriers might be less susceptible to infection of and mortality due to COVID-19. Further research should focus on the interaction between DBP and its polymorphisms, vitamin D, and SARS-CoV-2 infection.

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