key: cord-298542-4du3gar7
authors: Karcioglu Batur, Lutfiye; Hekim, Nezih
title: The role of DBP gene polymorphisms in the prevalence of new coronavirus disease 2019 infection and mortality rate
date: 2020-08-16
journal: J Med Virol
DOI: 10.1002/jmv.26409
sha: 
doc_id: 298542
cord_uid: 4du3gar7

Since December 2019, coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2, has given rise to emerging respiratory infections with pandemic diffusion. The vitamin D binding protein (DBP) with emphasis on its regulation of total and free vitamin D metabolite levels participate in various clinical conditions. The main goal of this study was to evaluate if there was any association between the DBP gene polymorphism at rs7041 and rs4588 loci and the prevalence of COVID‐19 and its mortality rates caused among populations of 10 countries including Turkey. Positive significant correlations were found between the prevalence (per million) and mortality rates (per million), and GT genotype (P < .05) while there was a negative significant correlation between prevalence (per million) and mortality rates (per million), and TT genotype at rs7041 locus among all populations (P < .05). However, no significant correlation was found at rs4588 locus. GT genotype was found to confer this susceptibility to the populations of Germany, Mexico, Italy, Czech, and Turkey. The variations in the prevalence of COVID‐19 and its mortality rates among countries may be explained by Vitamin D metabolism differed by the DBP polymorphisms of rs7041 and rs4588.

Since December 2019, coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has given rise to emerging respiratory infections with a pandemical diffusion. 1 By 2 July 2020, the global number of confirmed cases of COVID-19 reached 10 534 765 with a mortality of 512 881. 2 In Turkey, 201 098 cases and 5150 deaths have been confirmed until 2nd July 2020. 2 A relationship was recently found between vitamin D levels and the number COVID-19 cases and the mortality rates caused by the coronavirus infection. 3 The vitamin D binding protein (DBP) with emphasis on its regulation of total and free vitamin D metabolite levels participate in various clinical conditions. Nearly all DBP is produced in the liver, where its regulation is influenced by estrogen, glucocorticoids, and inflammatory cytokines but not by vitamin D itself. DBP is the most polymorphic protein known, and different DBP alleles can have substantial impact on its biologic functions. 4 The two most common alleles-Gc1s (rs7041 locus) and Gc2 (rs4588 locus)-differ in their affinity with the vitamin D metabolites and have been variably associated with several clinical conditions. 4 Among these conditions, G allele at the rs7041 locus was found to be related with increased susceptibility to hepatitis C viral infection. 5 Moreover, the individuals having an AA genotype within rs4588 locus of the Gc2 polymorphic region showed a greater increase at 25(OH)D levels following vitamin D supplementation than those having the GG genotype. 6 A single-nucleotide polymorphism at rs4588 has been associated with susceptibility to the metabolic syndrome. 7 Therefore, we hypothesized that DBP polymorphisms may play a significant role in COVID-19.

The main goal of this study was to evaluate if there is any association between the DBP gene polymorphism at rs7041 and rs4588 loci and the prevalence of COVID-19 and its mortality rates caused among populations of ten countries including Turkey.

To test this hypothesis and to limit confounding bias (latitude, etc), we focused on the countries whose DBP polymorphisms at rs7041 and rs4588 loci were defined and the allele frequencies reported in five cohort and two systematic review and meta-analysis studies. [8] [9] [10] [11] [12] [13] [14] [15] We searched the literature for DBP gene polymorphism in each country. We recorded the total number of cases of COVID-19 and per million population in each of the countries to find the prevalence, and the mortality rates caused by the coronavirus infection recorded at 2nd July 2020 (Table 1) 

Coronavirus disease (COVID-19) Situation Report-164. 2 The allele frequencies of DBP polymorphisms at rs7041 and rs4588 loci of Turkish population were retrieved from a previous thesis study (unpublished results). 16 The ethical approval for analyzing the blood samples to examine the polymorphisms was ob- Correlation between rs7041 and rs4588 polymorphisms and prevalence of COVID-19 and mortality rates per country demonstrated that there were positive significant correlations between the prevalence (per million) and mortality rates (per million), and GT genotype (P < .05), while there was a negative significant correlation between prevalence (per million) and mortality rates (per million),

and TT genotype at rs7041 locus among all populations (P < .05).

However, no significant correlation was found between the prevalence (per million) and mortality rates (per million), and the polymorphism at rs4588 locus (Table 2 ).

In the present study, TT genotype was found to confer COVID-19

susceptibility to the populations of China, Japan, Nigeria, and Kenya.

GT genotype was found to confer this susceptibility to the popula- Vitamin D plays a major role in regulating the immune system, including immune responses to viral infection. 24 Interventional and observational epidemiological studies provide evidence that vitamin D deficiency may confer an increased risk of influenza and respiratory tract infection. 25 Cell culture experiments support the thesis that vitamin D has direct antiviral effects particularly against enveloped viruses. Though vitamin D's antiviral mechanism has not been fully established, it may be linked to vitamin D's ability to upregulate the antimicrobial peptides LL-37 and human beta-defensin 2. 26 Regarding the genetic susceptibility to a viral infection in vitamin D deficiency, we also observed significant correlations between rs7041 polymorphism and prevalence of COVID-19 and mortality rates per country.

However, no significant correlation was found between the prevalence (per million) and mortality rates (per million) at rs4588 locus.

The pathology of COVID-19 involves a complex interaction between the SARS-CoV-2 and the body immune system. Calcitriol (1,25dihydroxyvitamin D3) exerts pronounced impacts on ACE2/Ang(1-7)/ MasR axis with enhanced expression of ACE2. 27 ACE2 is the host cell receptor responsible for mediating infection by SARS-CoV-2. ACE2

polymorphisms were recently described in human populations. 28 Another common polymorphism was found in DBP gene, which is a highly polymorphic gene. Allelic variants of the DBP gene have been studied extensively for their association with vitamin D deficiency 29, 30 and viral infections. 5 Two of these variants corresponding to different allelic arrangements of rs7041 and rs4588 were reported to have a different 

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Posttraumatic stress disorder is associated with reduced vitamin D levels and functional polymorphisms of the vitamin D binding-protein in a population-based sample

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