Role of FokI rs2228570 and Tru9I rs757343 Polymorphisms in the Mortality of Patients Infected with Different Variants of SARS-CoV-2.

BACKGROUND AND AIM: Low vitamin D levels are associated with the severity of coronavirus disease 19 (COVID-19). Vitamin D receptor gene polymorphisms, such as Tru9I rs757343 and FokI rs2228570, have been suggested to be potential risk factors for severe COVID-19 outcomes. This study investigated how Tru9I rs757343 and FokI rs2228570 polymorphisms influenced the mortality rate of COVID-19 in relation to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. METHODS: The polymerase chain reaction-restriction fragment length polymorphism assay was used to genotype Tru9I rs757343 and FokI rs2228570 genotypes in 1,734 recovered and 1,450 deceased patients. RESULTS: Our results demonstrated that the high mortality rate was correlated with FokI rs2228570 TT genotype in all three variants but was much higher in the Omicron BA.5 variant than in the Alpha and Delta variants. Furthermore, in patients infected with the Delta variant, FokI rs2228570 CT genotype was more highly correlated with the mortality rate compared to other variants. Thus, a high mortality rate was correlated with the Tru9I rs757343 AA genotype in the Omicron BA.5 variant, whereas this relationship was not observed in the other two variants. The T-A haplotype was related to COVID-19 mortality in all three variants, but its effect was more pronounced in the Alpha variant. Moreover, the T-G haplotype was significantly associated with all three variants. CONCLUSION: Our findings showed that the effects of Tru9I rs757343 and FokI rs2228570 polymorphisms were related to SARS-CoV-2 variants. However, further studies are still required to validate our findings.

Plasma 25-Hydroxyvitamin D Level and VDR Gene Single Nucleotide Polymorphism rs2228570 Influence on COVID-19 Susceptibility among the Kazakh Ethnic Group-A Pilot Study.

Low plasma levels of the vitamin D metabolite 25-hydroxyvitamin D [25(OH)D] and the vitamin D receptor (VDR) gene single nucleotide polymorphisms (SNPs) have been associated with the body's susceptibility to infectious diseases, including COVID-19. In this pilot retrospective study, representatives of the Kazakh population (central Kazakhstan) were divided into groups based on the test for IgM and IgG for coronavirus infection. We compared the 25(OH)D plasma levels and concluded that the COVID-19-positive group values (25.17 ng/mL ± 16.65) were statistically lower (p = 0.0114) compared to the COVID-19-negative ones (35.58 ng/mL ± 20.67). There was no association between age, gender and 25(OH)D concentration within the groups (p > 0.05). The genotyping of rs2228570 was performed using a TaqMan Real-Time PCR assay. Allele C predominated among the COVID-19-negative participants and significantly reduced the likelihood of coronavirus infection (p < 0.0001; OR = 0.0804; 95% CI 0.02357-0.2798). There were no statistically significant differences in the frequencies of the A, G and T alleles in the studied groups (p > 0.05). The GG genotype of rs2228570 was associated with a 4.131-fold increased likelihood of COVID-19 infection (p = 0.0288; χ2 = 5.364; OR = 4.131; 95% CI 1.223-13.71). Comprehensive studies are required to determine whether low 25(OH)D plasma concentrations and genetic background represent a risk factor for COVID-19 infection.

The role of vitamin D receptor and IL-6 in COVID-19.

BACKGROUND: Vitamin D (Vit.D) has an important role in protecting COVID-19 patients. This study investigated the changes in vitamin D receptor (VDR) expression and interleukin 6 levels in patients with COVID-19. MATERIALS AND METHODS: 120 hospitalized patients and 120 healthy people participated in this study, both group adjusted by sex and age. Vit.D was measured with HPLC, the expression of VDR gene was done with Real-time PCR, and IL-6 was measured with ELISA assay. RESULTS: Our findings showed no significant difference in the case of Vit.D (25-OH-D3) between the two studied groups, interestingly the expression of VDR was statistically lower in the patients with COVID-19, p-value = 0.003. VDR expression was lower in the patient with diabetes, hypertension and cardiovascular disease, significantly, p-value = 0.002. The level of IL-6 was statistically higher in the COVID-19 group, p-value = 0.003. CONCLUSION: Alongside the important role of 25-OH-D3 in COVID-19 patients, the quality and quantity of the VDR expression and its role in the level of IL-6 are the promising risk factors in the future. Further studies are needed to determine the factors increasing the expression level of VDR, especially in the patients with diabetes, hypertension and cardiovascular disease.

Editorial of Special Issue "The Role of Vitamin D in Human Health and Diseases 2.0".

Vitamin D performs a differentiating, metabolic and anti-inflammatory function, through genomic, non-genomic and mitochondrial mechanisms of action [...].

Association of ApaI rs7975232 and BsmI rs1544410 in clinical outcomes of COVID-19 patients according to different SARS-CoV-2 variants.

A growing body of research has shown how important vitamin D is in the prognosis of coronavirus disease 19 (COVID-19). The vitamin D receptor is necessary for vitamin D to perform its effects, and its polymorphisms can help in this regard. Therefore, we aimed to evaluate whether the association of ApaI rs7975232 and BsmI rs1544410 polymorphisms in different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants were influential in the outcomes of COVID-19. The polymerase chain reaction-restriction fragment length polymorphism method was utilized to determine the different genotypes of ApaI rs7975232 and BsmI rs1544410 in 1734 and 1450 patients who had recovered and deceased, respectively. Our finding revealed that the ApaI rs7975232 AA genotype in the Delta and Omicron BA.5 and the CA genotype in the Delta and Alpha variants were associated with higher mortality rate. Also, the BsmI rs1544410 GG genotype in the Delta and Omicron BA.5 and the GA genotype in the Delta and Alpha variants were related to a higher mortality rate. The A-G haplotype was linked with COVID-19 mortality in both the Alpha and Delta variants. The A-A haplotype for the Omicron BA.5 variants was statistically significant. In conclusion, our research revealed a connection between SARS-CoV-2 variants and the impacts of ApaI rs7975232 and BsmI rs1544410 polymorphisms. However, more research is still needed to substantiate our findings.

Association of CYP24A1 Gene rs6127099 (A > T) Polymorphism with Lower Risk to COVID-19 Infection in Kazakhstan.

In December 2019, SARS-CoV-2 was identified in Wuhan, China. Infection by SARS-CoV-2 causes coronavirus disease 2019 (COVID-19), which is characterized by fever, cough, dyspnea, anosmia, and myalgia in many cases. There are discussions about the association of vitamin D levels with COVID-19 severity. However, views are conflicting. The aim of the study was to examine associations of vitamin D metabolism pathway gene polymorphisms with symptomless COVID-19 susceptibility in Kazakhstan. The case-control study examined the association between asymptomatic COVID-19 and vitamin D metabolism pathway gene polymorphisms in 185 participants, who previously reported not having COVID-19, were PCR negative at the moment of data collection, and were not vaccinated. A dominant mutation in rs6127099 (CYP24A1) was found to be protective of asymptomatic COVID-19. Additionally, the G allele of rs731236 TaqI (VDR), dominant mutation in rs10877012 (CYP27B1), recessive rs1544410 BsmI (VDR), and rs7041 (GC) are worth consideration since they were statistically significant in bivariate analysis, although their independent effect was not found in the adjusted multivariate logistic regression model.

Evaluating the Role of BglI rs739837 and TaqI rs731236 Polymorphisms in Vitamin D Receptor with SARS-CoV-2 Variants Mortality Rate.

A lack of vitamin D is a potential risk factor for coronavirus disease (COVID-19). Variants in the Vitamin D Receptor (VDR) gene, such as BglI rs739837 and TaqI rs731236, are associated with various viral infection progressions. This study aimed to evaluate the relationship between the BglI rs739837 and TaqI rs731236 polymorphisms and the mortality rate of COVID-19 based on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. The genotyping of BglI rs739837 and TaqI rs731236 genotypes was analyzed using the polymerase chain reaction-restriction fragment length polymorphism in 1734 improved and 1450 deceased patients positive for SARS-CoV-2. In this study, the rate of COVID-19 mortality was correlated with TaqI rs731236 TC and CC in the α variant and with TaqI rs731236 CC in the Delta variant, whereas no relationship was found in the Omicron BA.5 variant. In addition, the rate of COVID-19 mortality was associated with BglI rs739837 GT and TT in the Omicron BA.5 variant, while there was no association between BglI rs739837 and COVID-19 mortality in the α and Delta variants. The TG haplotype was more common in all SARS-CoV-2 variants, while the CT haplotype was associated with COVID-19 mortality in the Delta and Omicron BA.5 variants. In conclusion, this study indicated that the impacts of BglI rs739837 and TaqI rs731236 polymorphisms were related to SARS-CoV-2 variants. However, further research is still needed to approve our findings.

A Novel Immunomodulatory Mechanism by Which Vitamin D Influences Folate Receptor 3 Expression to Reduce COVID-19 Severity.

BACKGROUND/AIM: Identify potential mechanisms involving gene expression changes through which vitamin D supplementation could be beneficial in preventing adverse COVID-19 outcomes. MATERIALS AND METHODS: We performed a literature review to identify differentially expressed genes (DEGs) in the blood between severe and mild COVID-19 patients. We compared these with the top DEGs induced by 6 months of 10,000 IU/day vitamin D supplementation in healthy adults who were vitamin D deficient/insufficient. We used bioinformatic tools to look for a vitamin D response element (VDRE) in DEGs. RESULTS: FOLR3, RGS1, GPR84, and LRRN3 were the most significantly altered genes by 6 months of 10,000 IU/day vitamin D supplementation whose expression levels were also involved in COVID-19 severity. FOLR3 and GPR84 were found to be consistently up-regulated and RGS1 and LRRN3 consistently down-regulated in severe COVID-19 infection. FOLR3 and LRRN3 were down-regulated and RGS1 and GPR84 were up-regulated by 10,000 IU/day vitamin D supplementation. CONCLUSION: FOLR3 and RGS1 are expressed in neutrophils and lymphocytes, respectively. Vitamin D supplementation may decrease the neutrophil-lymphocyte ratio as has been reported in patients admitted with severe symptoms. There is evidence that vitamin D directly influences the expression of the RGS1 gene through vitamin D receptor binding. A potential negative VDRE (nVDRE) in an intron of the FOLR3 gene was found, which was homologous with two known nVDREs. Combined with other transcription factor elements near the newly identified nVDRE, these observations may explain the mechanism by which vitamin D regulates these genes, thus influencing COVID-19 outcomes.

Relationship between Acute Respiratory Tract Infection and the Serum 25(OH) D3 Level in Chronic Kidney Disease Patients and Its Prevention and Treatment.

Observational studies and randomized controlled studies propose that vitamin D plays a significant role in preventing acute respiratory tract infection (RTI); however, results are inconsistent and the optimal serum 25-hydroxyvitamin D (25-OH-D3) concentration remains unknown. This study explores the risk factors associated with acute RTI in patients with chronic kidney disease (CKD) and analyzes its correlation with serum 25-OH-D3 levels, to provide appropriate preventive treatment measures for CKD patients complicated with acute RTI. Seventy cases of CKD patients treated in the department of nephrology of Jiangxi Provincial People's Hospital are recruited as the research objects and divided into a control group (CKD without RTI) and an observation group (CKD with RTI), with 35 cases in each group. The laboratory indexes and serum 25-OH-D3 levels are compared between the two groups. The area under the receiver operating characteristic curve (ROC) of 25-OH-D3 in the diagnosis of CKD patients complicated with RTI is 0.892, and the standard error is 0.038. The glomerular filtration rates (GFR) are 48.32 ± 9.87 mL/min and 50.18 ± 20.71 mL/min in the control group and the experimental group, respectively, with no statistical significance between the two groups (P > 0.05). The serum 25-OH-D3 content in the control group (35.08 ± 6.2 nmol/L) is dramatically higher than that in the observation group (20.71 ± 5.87 nmol/L) (P < 0.05). The proportion of patients with diabetes mellitus (DM) in the control group and observation group is 25.71% and 68.57%, respectively, with a considerable difference (P < 0.05). In the control group and the experimental group, the proportion of patients with oral vitamin D receptor agonists is 54.29% and 11.43%, respectively, and the difference is significant (P < 0.05). Results show that the serum 25-OH-D3 level is highly correlated with the occurrence of RTI in CKD patients. In addition, it is related to patients' age, DM, and vitamin D receptor agonists.

VDR gene polymorphisms are associated with the increased susceptibility to COVID-19 among iranian population: A case-control study.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the pathogenesis is unclear. Host genetic background is one of the main factors influencing the patients' susceptibility to several viral infectious diseases. This study aimed to investigate the association between host genetic polymorphisms of two genes, including vitamin D receptor (VDR) and vitamin D binding protein (DBP), and susceptibility to COVID-19 in a sample of the Iranian population. This case-control study enrolled 188 hospitalized COVID-19 patients as the case group and 218 suspected COVID-19 patients with mild signs as the control group. The VDR (rs7975232, rs731236 and rs2228570) and DBP (rs7041) gene single nucleotide polymorphisms (SNPs) were genotyped by Polymerase Chain Reaction Restriction - Fragment Length Polymorphism (PCR-RFLP) method. A significant association between rs2228570 SNP in the VDR gene and the susceptibility of COVID-19 was found between case and control groups. The CT genotype (Heterozygous) of rs2228570 C > T polymorphism showed significant association with a 3.088 fold increased odds of COVID-19 (p < .0001; adjusted OR: 3.088; 95% CI: 1.902-5.012). In addition, a significant association between CC genotype of rs2228570 CT polymorphism and increased odds of COVID-19 in male and female groups (p = .001; adjusted OR: 3.125; 95% CI: 1.630-5.991 and p = .002; adjusted OR: 3.071; 95% CI: 1.485-6.354 respectively) were determined. Our results revealed no significant differences in the frequency of genotype and allele of VDR (rs7975232 and rs731236) and DBP (rs7041) between SARS-CoV-2-infected patients and controls (p > .05). Our results showed that polymorphism of VDR (rs2228570) probably could influence individual susceptibility to COVID-19. The polymorphisms of VDR (rs7975232 and rs731236) and DBP (rs7041) were not associated with SARS-CoV-2 infection susceptibility.

Modifying effects of TNF-α, IL-6 and VDR genes on the development risk and the course of COVID-19. Pilot study.

OBJECTIVES: COVID-19 continues to range around the world and set morbidity and mortality antirecords. Determining the role of genetic factors in the development of COVID-19 may contribute to the understanding of the pathogenetic mechanisms that lead to the development of complications and fatalities in this disease. The aim of our study was to analyze the effect of TNF-α (rs1800629), IL-6 (rs1800795) and VDR (rs731236 and rs1544410) genes variants on the development risk and the course of COVID-19 in intensive care patients. METHODS: The study group included 31 patients with diagnosis "viral COVID-19 pneumonia". All patients underwent standard daily repeated clinical, instrumental and laboratory examinations. Determination of IL-6, TNF-α, and VDR genes variants was performed using the PCR-RFLP method. RESULTS: It was found a significant increase in the rate of the CC genotype and C allele (38.7 vs. 12.0% and 0.6 vs. 0.4%, respectively) of the IL-6 gene in all patients of the study in comparison with population frequencies. There was a significantly higher rate of heterozygous genotypes TC and GA of the VDR gene in group of died patients. The rs1800629 variant of the TNF-α gene is associated with the need for respiratory support and its longer duration in patients with COVID-19. CONCLUSIONS: The obtained results support a hypothesis about the influence of variants of IL-6, TNF-α and VDR genes on severity of COVID-19. However, in order to draw definite conclusions, further multifaceted research in this area are need.

Calcifediol for Use in Treatment of Respiratory Disease.

Calcifediol is the prohormone of the vitamin D endocrine system (VDES). It requires hydroxylation to move to 1,25(OH)2D3 or calcitriol, the active form that exerts its functions by activating the vitamin D receptor (VDR) that is expressed in many organs, including the lungs. Due to its rapid oral absorption and because it does not require first hepatic hydroxylation, it is a good option to replace the prevalent deficiency of vitamin D (25 hydroxyvitamin D; 25OHD), to which patients with respiratory pathologies are no strangers. Correcting 25OHD deficiency can decrease the risk of upper respiratory infections and thus improve asthma and COPD control. The same happens with other respiratory pathologies and, in particular, COVID-19. Calcifediol may be a good option for raising 25OHD serum levels quickly because the profile of inflammatory cytokines exhibited by patients with inflammatory respiratory diseases, such as asthma, COPD or COVID-19, can increase the degradation of the active metabolites of the VDES. The aim of this narrative revision is to report the current evidence on the role of calcifediol in main respiratory diseases. In conclusion, good 25OHD status may have beneficial effects on the clinical course of respiratory diseases, including COVID-19. This hypothesis should be confirmed in large, randomized trials. Otherwise, a rapid correction of 25(OH)D deficiency can be useful for patients with respiratory disease.

Editorial of Special Issue "The Role of Vitamin D in Human Health and Diseases".

Vitamin D has been described as a differentiative hormone, but this definition is reductive for a molecule targeting every tissue, produced in its active form by many kinds of cells and effective on the whole life of cells by different mechanisms, which lead to nuclear, non-genomic and mitochondrial effects [...].

Immunohistochemical Expression of VDR in Myocardium: Postmortem Evaluation of COVID-19 Patients.

Morphological data on heart damage and its mechanisms due to extremely severe course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are limited, as well as data on the correlation of damage and expression of vitamin D receptors (VDRs). In this study, we analyzed a series of myocardial samples obtained during postmortem autopsy of 48 critically ill patients with COVID-19 who died with SARS-CoV-2-associated pneumonia. The purpose of the study was to evaluate immunohistochemical VDR expression in the myocardium. The results showed the only minimal or no immunohistochemical expression of VDR in the nuclei of cardiomyocytes in most cases, along with the persisted strong expression in lymphoid cells. To the best of our knowledge, it is the first study and data provided were regarding myocardial VDR expression in COVID-19 patients. The results are of interest in terms of further study of the effects of ligand-associated VDR activation on the cardiovascular system.

Effects of vitamin D receptor gene polymorphisms on the prognosis of COVID-19.

PURPOSE: Vitamin D deficiency has emerged as another potential risk factor for coronavirus disease (COVID-19) due to the immunomodulatory effects of 25 hydroxyvitamin D [25 (OH)D]. Vitamin D receptor (VDR) gene polymorphisms such as Fok I, Bsm I, Apa I, and Taq I are also associated with different courses of viral infections. This study aimed to evaluate the association between the VDR gene polymorphism at Fok I, Taq I, Bsm I, and Apa I genotypes and the prognosis of COVID-19 in respect to vitamin D deficiency. METHODS: Two-hundred ninety-seven patients with COVID-19 were enrolled. Serum 25 (OH)D levels were measured. Four variant regions of the VDR gene, FokI, BsmI, ApaI, and TaqI were determined. RESULTS: Eighty-three percent of subjects had vitamin D deficiency, and 40.7% of the whole group had severe deficiency. Median 25 (OH)D level was 11.97 ng/ml. Vitamin D levels were not related to inflammatory markers, disease severity, admission to intensive care unit (ICU), and mortality. While disease severity was related to Fok I Ff genotype, it was Taq TT genotype for ICU admission. Moreover, the ApaI aa genotype was common among the patients who were died. None of the deceased subjects had the Fok I FF genotype. CONCLUSION: 25 (OH)D levels were not related to the severity and mortality of COVID-19. VDR gene polymorphisms are independently associated with the severity of COVID-19 and the survival of patients.

Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells.

The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.

The Effects of Vitamin D on Immune System and Inflammatory Diseases.

Immune cells, including dendritic cells, macrophages, and T and B cells, express the vitamin D receptor and 1α-hydroxylase. In vitro studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, has an anti-inflammatory effect. Recent epidemiological evidence has indicated a significant association between vitamin D deficiency and an increased incidence, or aggravation, of infectious diseases and inflammatory autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. However, the impact of vitamin D on treatment and prevention, particularly in infectious diseases such as the 2019 coronavirus disease (COVID-19), remains controversial. Here, we review recent evidence associated with the relationship between vitamin D and inflammatory diseases and describe the underlying immunomodulatory effect of vitamin D.