Vitamin D Receptor Variants Research Articles

Association of VDR Polymorphisms with Muscle Mass Development in Elite Young Soccer Players: A Pilot Study.

The vitamin D receptor (VDR) is an important candidate gene in musculoskeletal phenotypes. Polymorphisms in the VDR have been previously associated with several pathologies and muscular strength in athletes and elderly people; however, the literature reported contradictory results. The object of this research was to verify the association between the most studied VDR variants (rs2228570, rs7975232, and rs1544410) and the increase in muscle mass in elite young soccer players. A sample of 55 soccer players (15-18 years old) from a professional team were selected for this study. DNA was extracted by the salting-out method, and polymorphisms were genotyped by PCR-RFLP, followed by 2% agarose gel electrophoresis. To test the effect of the three SNPs (single nucleotide polymorphisms), a logistic regression analysis was applied. The body composition determination was carried out through the skinfold thickness method, and the muscular area of the arm and lower limb were calculated using the Frisancho formula. All three polymorphisms met the Hardy-Weinberg equilibrium (p > 0.05) and their frequencies fell within the worldwide variability. A significant correlation between rs1544410 and the increase in calf muscle mass was observed. Individuals carrying the A allele showed higher calf muscular mass than those carrying the G allele (p = 0.034). Moreover, a haplotype analysis applied to the two SNPs in linkage disequilibrium (rs7975232 and rs1544410) showed that the AG haplotype appeared negatively correlated to the calf muscle area. In conclusion, we confirm an association between VDR polymorphisms and muscular mass that could encourage the genetic screening of the VDR gene to identify a potential risk of injury and for individual nutritional interventions.

Effect of VDR and TLR2 gene variants on the clinical course of patients with COVID-19 disease.

The coronavirus disease 2019 (COVID-19) pandemic, which has caused a major global health crisis, primarily targets the upper and lower respiratory tract. But infected individuals may experience different clinical symptoms, ranging from asymptomatic to critical. The vitamin D receptor (VDR) and Toll-like receptor 2 (TLR2) polymorphisms play a role in the immune response. This study aimed to evaluate the effect of VDR Bsml (rs1544410) and TLR2 23bp indel variants on the clinical status of Turkish patients with COVID-19 disease. A total of 312 people, including 106 intensive care unit (ICU) patients, 103 symptomatic hospitalized patients, and 103 healthy controls, were included in the study. The VDR BsmI and TLR2 23bp indel were genotyped using polymerase chain reaction and/or restriction fragment length fraction methods. The VDR BsmI b/b genotype and b allele were higher in symptomatic patients compared to the healthy control group (p = 0.035). The VDR BsmI B/B and B/b genotype distribution did not differ between ICU patients and both symptomatic patients and controls (p > 0.05). We found that B/B:B/b+b/b and B/B+B/b:b/b were significantly different in symptomatic patients compared to controls (p = 0.033 and p = 0.041, respectively). The VDR BsmI b/b genotype distribution was found to be lower in deceased patients than in living patients (p = 0.023). There was no significant difference between the groups in terms of TLR2 23bp indel genotype and allele distribution (p > 0.05). Our study results suggest that the VDR BsmI b allele may have a role in COVID-19 patients with symptomatic findings. These data need to be repeated in different ethnic and larger sample groups.

Serum 25-hydroxyvitamin D concentrations, vitamin D receptor polymorphisms, and risk of infections among individuals with type 2 diabetes: a prospective cohort study

BackgroundEvidence on the association between serum 25-hydroxyvitamin D [25(OH)D] and infections among patients with type 2 diabetes (T2D), a group susceptible to vitamin D deficiency and infections, is limited. ObjectivesWe aimed to examine this association in individuals with T2D, and to evaluate whether genetic variants in vitamin D receptor (VDR) would modify this association. MethodsThis study included 19,851 participants with T2D from United Kingdom Biobank. Infections were identified by linkage to hospital inpatient and death registers. Negative binomial regression models were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs), with adjustment of potential confounders. ResultsIn patients with T2D, the incidence rate of infections was 29.3/1000 person-y. Compared with those with 25(OH)D of 50.0–74.9 nmol/L, the multivariable-adjusted IRRs and 95% CIs of total infections, pneumonia, gastrointestinal infections, and sepsis were 1.44 (1.31, 1.59), 1.49 (1.27, 1.75), 1.47 (1.22, 1.78), and 1.41 (1.14, 1.73), respectively, in patients with 25(OH)D <25.0 nmol/L. Nonlinear inverse associations between 25(OH)D concentrations and the risks of total infections (P-overall < 0.001; P-nonlinear = 0.002) and gastrointestinal infections (P-overall < 0.001; P-nonlinear = 0.040) were observed, with a threshold effect at ∼50.0 nmol/L. The vitamin D-infection association was not modified by genetic variants in VDR (all P-interaction > 0.050). ConclusionsIn patients with T2D, lower serum 25(OH)D concentration (<50 nmol/L) was associated with higher risks of infections, regardless of genetic variants in VDR. Notably, nonlinear inverse associations between 25(OH)D concentrations and the risks of infections were found, with a threshold effect at ∼50.0 nmol/L. These findings highlighted the importance of maintaining adequate vitamin D in reducing the risk of infections in patients with T2D.

Molecular investigation of vitamin D receptor (VDR) genetic variants and their impact on VDR mRNA and serum vitamin D levels in allergic rhinitis in an Indian population: A case-control study.

Vitamin D deficiency is widespread and poses a significant health concern, as emerging research links it to allergic diseases owing to its immunomodulatory functions. The optimal functioning of vitamin D and its activation depend on its nuclear receptor, vitamin D receptor (VDR). Genetic variants of VDR have been explored as potential factors in autoimmune and allergic diseases, with limited studies on their association with allergic rhinitis (AR). The present investigation aims to analyse the role of three VDR genetic variants - TaqI, FokI and BsmI - in AR susceptibility and their impact on VDR mRNA and serum vitamin D levels. A total of 550 subjects, consisting of 250 AR cases and 300 age- and gender-matched controls, underwent genotyping by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). VDR mRNA and vitamin D levels were determined by quantitative real-time PCR and chemiluminescence, respectively. Although TaqI did not exhibit significant differences, FokI demonstrated a noteworthy association with AR, particularly with the CC genotype (odds ratio [OR]: 3.34; confidence interval [CI]: 1.79-6.23). Similarly, BsmI revealed an increased risk for AR, with the GA+AA genotypes showing a 2.2-fold elevated risk (OR: 2.20; CI: 1.53-3.16). VDR mRNA expression was threefold lower in AR patients (p<.0001), accompanied by reduced serum vitamin D levels (p<.0001). In addition, CC (p=.01) and AA (p=.02) genotypes of FokI and BsmI were associated with reduced VDR mRNA levels, whereas TaqI showed no such association. Similarly, heterozygous genotypes of TaqI and FokI, as well as homozygous AA of BsmI, correlated with lower serum vitamin D levels (p<.001). This study emphasizes the intricate relationship among VDR genetic variations, altered VDR activity, immune modulation and vitamin D metabolism in AR. Further research involving diverse populations is crucial for confirming and generalizing these findings, paving the way for personalized therapeutic interventions in vitamin D-related disorders.

Relationship between vitamin D receptor genotypes (FOK1rs2228570) and IL18 gene expression in sample of multiple sclerosis Iraqi patients

BACKGROUND: Multiple Sclerosis known as MS, this chronic inflammatory demyelinating condition affects the nervous system. It is a heterogenic and multifactorial disease. The goal of the current study was to investigate the relationship between MS patients’ IL18 gene expression and the vitamin D receptor gene polymorphism (FOK1rs2228570). OBJECTIVE: The aim of the study to investigate the association of vitamin D receptor (FOK1rs2228570) gene polymorphism and pro inflammatory cytokine (IL18) gene expression among multiple sclerosis Iraqi patients. Detection VDR polymorphism and determine whether this SNP is involved in susceptibility to multiple sclerosis and estimation IL18 gene expression and explore its relation with multiple sclerosis susceptibility. METHODS: Blood samples were taken from 75 MS patients in Iraq (30 men and 45 women), as well as from 75 volunteers who seemed to be in a favorable state of health and fell within the age range of 20 to 50 years. Tetra-ARMS Polymerase Chain Reaction (Tetra-ARMS PCR) was used to find polymorphisms in the vitamin D receptor (VDR) gene, and Real-time Polymerase Chain Reaction (RT-PCR) was used to measure IL18 gene expression. RESULTS: The findings from the analysis of VDR gene polymorphism in patients with MS indicated that the wild-type genotype T/T was present in 8 individuals, accounting for 10.6%, the heterogeneous genotype TC was 36 (48%), and the homogeneous genotype CC was 31 (41.3%), whilst T allele frequency was 52(34.6%) and C allele was 98(65.3%) with (P⩽ 0.01) significant difference and even as in control T/T genotype was 49(65.3%), TC genotype was 21(28%), CC genotype was 5(6.66%), T allele frequency was 119(79.3%) and C allele was 31(20.6%) with significant difference (P⩽ 0.001). While estimation of IL18 expression showed high elevation in patients’ group (2.59 ± 0.51 fold) by significance difference (P⩽ 0.5) when compared to control group (1.35 ± 0.14 fold). The relationship between IL18 gene expression with VDR variant in MS patients demonstrated a significant rise (2.9 ± 0.51 fold) at CC genotype patients in IL18 folding gene expression, followed by (4.6 ± 0.17 fold) in TC genotype patients and finally (1.4 ± 0.08 fold) in TT genotype patients with highly significant (P⩽ 0.01). CONCLUSION: The VDR(FOK1rs2228570) genotype was significantly correlated with IL18 expression in MS patients from Iraq.

Vitamin D Deficiency and Its Association With Vitamin D Receptor Gene Variants Among Malaysian Women With Hypertensive Disorders in Pregnancy: Protocol for a Nutrigenomics Study.

Vitamin D deficiency has been associated with hypertensive disorders in pregnancy (HDP). The risk of developing HDP was reported to be further augmented among individuals with a vitamin D receptor (VDR) genetic variant. However, the reported roles of VDR variants in hypertensive disorders are inconsistent among different populations. Given the relatively higher incidence of vitamin D deficiency among Malaysian pregnant women and the high incidence of HDP in this population, we hypothesize that there may be associations between the risk of vitamin D deficiency and HDP with VDR genetic variants. This paper outlines the protocol for a study to determine the association of vitamin D status and VDR sequence variants among Malaysian pregnant women with HDP. This prospective study consists of two phases. The first phase is a cross-sectional study that will entail gathering medical records, a questionnaire survey, and laboratory testing for vitamin D status, with a planned recruitment of 414 pregnant women. The questionnaire will be utilized to assess the risk factors for vitamin D deficiency. The vitamin D status will be obtained from measurement of the vitamin D (25-hydroxyvitamin D3) level in the blood. The second phase is a case-control study involving a Malay ethnic cohort with vitamin D deficiency. Participants will be divided into two groups with and without HDP (n=150 per group). Genomic DNA will be extracted from the peripheral blood monocytes of participants using the Qiagen DNA blood kit, and VDR sequence variants will be determined using polymerase chain reaction-high-resolution melting (PCR-HRM) analysis. Sanger sequencing will then be used to sequence randomly selected samples corresponding to each identified variant to validate our PCR-HRM results. The VDR genotype and mutation frequencies of BsmI, ApaI, TaqI, and FokI will be statistically analyzed to evaluate their relationships with developing HDP. As of December 2023, 340 subjects have been recruited for the phase 1 study, 63% of whom were determined to have vitamin D deficiency. In the phase 2 study, 50 and 22 subjects have been recruited from the control and case groups, respectively. Recruitment is expected to be completed by March 2024 and all analyses should be completed by August 2024. The outcome of the study will identify the nonmodifiable genetic components contributing to developing vitamin D deficiency leading to HDP. This will in turn enable gaining a better understanding of the contribution of genetic variability to the development of HDP, thus providing more evidence for a need of customized vitamin D supplementation during pregnancy according to the individual variability in the response to vitamin D intake. ClinicalTrials.gov NCT05659173; https://clinicaltrials.gov/study/NCT05659173. DERR1-10.2196/53722.

Clinical and genetic determinants of vitamin D receptor expression in cutaneous melanoma patients.

Decrease of vitamin D receptor (VDR) expression is observed in melanocytic naevi and melanoma compared to normal skin. Little is known about factors influencing VDR expression in cutaneous melanoma (CM). We investigated the correlation of VDR expression in CM with 25-hydroxy vitamin D (25OHD) levels, demographic/clinical parameters, genetic variants of VDR and pathology of the primary tumor. Demographic/clinical parameters were recorded in 407 prospectively recruited CM patients of a multi-center controlled study (ViDMe trial). We determined VDR expression both in the nucleus and in the cytoplasm by semi-quantitative assessment in CM tissue using histochemistry in 279 patients, expressed in percentages and histoscore (H-score). Genomic DNA from 332 patients was extracted to genotype thirteen VDR single nucleotide polymorphisms (SNPs) using TaqMan. VDR expression in CM tissue from 279 patients was correlated with clinical/demographic parameters and 25OHD levels (univariable and multivariable analysis), VDR SNPs (univariable analysis) and pathology parameters of primary CM tissue (univariable analysis). Cytoplasmic VDR expression was increased in patients who stated to have a high sun exposure during their life compared to patients with low sun exposure (p H-score,univariable : 0.001, p H-score,multivariable : 0.004). The A allele of the genetic VDR polymorphism Fok1 was associated with a higher expression of the VDR in the cytoplasm (p cytoplasmic, univariable : 0.001 and p H-score, univariable : 0.02). In the primary tumor, presence of mitosis (p nucleus,%, univariable : 0.002) and perineural invasion (p nucleus,%,univariable : 0.03) were significantly associated with low nuclear VDR expression. ClinicalTrials.gov Identifier: NCT01748448.

The Vitamin D Receptor Bsm1 Variant is not Associated With Temporomandibular Disorder With or Without Bruxism

Background: Temporomandibular joint disorder (TMD), a set of conditions that affect the temporomandibular joint and related structures, is frequently linked to bruxism. The vitamin D receptor (VDR) affects calcium absorption, bone remodeling, and mineralization rate. The goal of this study was to evaluate the role of the VDR Bsm1 (rs1544410) variant in the susceptibility to bruxism in TMD.&#x0D; Method: A total of 321 people [221 TMD patients (135 with bruxism and 86 without bruxism) and 100 healthy controls] were included in the study. The VDR Bsm variant was genotyped using the PCR-RFLP method. &#x0D; Results: We found no significant difference between the all-TMD patient group and the control group regarding the VDR Bsm1 genotype and allele distribution (p&gt;0.05). There was no deviation from HWE for the VDR variant in groups. There was no relationship between pain characteristics and VDR Bsml genotype distribution in patients with bruxism.&#x0D; Conclusions: Our results support the conclusion that the VDR Bsm1 variant is not a risk factor for the development of bruxism in TMD. The effect of the VDR Bsml variant on the risk of bruxism in TMD should be investigated in studies involving larger populations and other ethnicities.

THU398 Variants In The Vitamin D Receptor, 1alpha-hydroxylase Enzyme Genes In Cholecalciferol Therapy

Abstract Disclosure: S. Kalinchenko: None. L. Vorslov: None. T. Shkeleva: None. A. Kahn: None. O. Samburskaya: None. The administration of vitamin D drugs should be done with regard to genetic analysis of polymorphisms in the vitamin D receptor (VDR) and 1alpha-hydroxylase enzyme (CYP27B1) genes to select the required dose, form and activity of the drug. Materials and Methods: In the period from 10.10.2020 to 23.12.2022 there were 936 patients aged from 2 to 77 years on therapy with cholecalciferol, in whom vitamin D status was determined by calcidiol mass spectrometry and parathormone in blood. Patients were genotyped for two markers of susceptibility to vitamin D deficiency: variants in the vitamin D receptor gene (VDR, BsmI Polymorphism, rs1544410) and the 1-alpha hydroxylase enzyme gene (CYP27B1, g.57764205A&amp;gt;G; rs4646536) by direct sequencing. Findings: Patients received therapy with cholecalciferol preparations. As a result, they were divided into 2 groups: the first group in which clinical effects of vitamin D deficiency compensation were achieved against the background of treatment, the second group in which, despite taking adequate selected doses, considering age, weight and degree of deficiency, laboratory criteria of vitamin D sufficiency were achieved, but clinical effects were not achieved. Genetic analysis showed that those patients in whom clinical symptoms of vitamin D deficiency were more severe and those in whom therapy with cholecalciferol did not produce the expected clinical effect had polymorphisms in the genes encoding VDR and/or 1alpha-hydroxylase enzyme. Discussion: In the presence of the CYP27B1 variant, g.57764205A&amp;gt;G; rs4646536 in the gene encoding 1alpha-hydroxylase (86.5% of all patients, n = 809), calcitriol formation is reduced, which explains the lack of effect of cholecalciferol therapy. In the presence of the VDR variant, BsmI Polymorphism, rs1544410 in the gene encoding the vitamin D receptor, sensitivity of the receptor to hormone D is reduced (13% of all patients, n = 122), which explains the lack of clinical effects of therapy with vitamin D drugs in standard therapeutic doses. And the most difficult to treat clinical manifestations of vitamin D deficiency occur in patients with polymorphisms in the two genes encoding both VDR and 1alpha-hydroxylase, which constituted 11.3% (n = 106) according to our study among all those examined. Conclusion: Conflicting literature data and clinical effects in vitamin D therapy are due to variants in the VDR and/or CYP27B1 genes. Knowledge of genetics is the individualized dose, form, and activity of vitamin D medication as the key to success in therapy. Presentation: Thursday, June 15, 2023

Association of vitamin D levels and VDR variant (rs2228570) with allergic rhinitis: A meta-analysis and trial sequential analysis

BackgroundAllergic rhinitis (AR) is a most common allergic condition characterised by cough, sneezing and flu-like symptoms. The aetiology of AR is not known. A deficiency of vitamin D has been associated with various allergic diseases. The role of vitamin D in allergic rhinitis has been explored in different populations, but the results remained inconsistent. Furthermore, vitamin D exerts its effect through the vitamin D receptor (VDR), and genetic variations in the VDR gene significantly alter vitamin D. We performed a meta-analysis to investigate the role of vitamin D levels and VDR polymorphisms with a predisposition to the development of AR. Materials and methodsAll published articles were searched using databases such as PubMed, Google Scholar, and Science Direct. Based on rigorous inclusion and exclusion, appropriate studies were identified. Vitamin D levels, VDR genotype and allele frequencies were extracted from the eligible reports. The meta-analysis was performed by comprehensive meta-analysis software v3.3. ResultsThe present meta-analysis comprised 14 reports with 1504 AR patients and 1435 healthy controls. Compared to healthy controls, AR had significantly lower levels of vitamin D (P = 0.000, standard difference of means = −1.287, 95% CI = −1.921 to −0.652). The meta-analysis of two separate investigations, which included 917 cases and 847 controls, showed no predisposition to allergic rhinitis. The trial sequential analysis also demonstrated the need for future case-control studies of VDR polymorphism to examine their involvement in AR. ConclusionsLower vitamin D levels are associated with allergic rhinitis, and vitamin D supplementation might be advantageous in addition to standard treatment. The connection of VDR polymorphism (rs2228570) remained equivocal, and additional research is needed. SummaryVitamin D exerct its beneficial effect through the vitamin D receptor (VDR) and role of vitamin D and VDR variant in the allergic rhinitis has been contradictories. We performed a meta-analysis to draw a definitive conclusion of importance of vitamin D and VDR polymorphisms in predisposition to development of allergic rhinitis. The observations of the meta-analysis revealed a significant association of lower vitamin D with allergic rhinitis. In addition the VDR rs2228570 variant predisposed subject to develop rhinitis. Collectively, the results of the present investigation redirect requirement of individualized vitamin D supplementation in the management of allergic rhinitis.

Hereditary Vitamin D-Resistant Rickets (HVDRR) associated SNP variants of vitamin D receptor exhibit malfunctioning at multiple levels

Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily. It is a primary regulator of calcium and phosphate homeostasis required for skeleton and bone mineralization. Vitamin D in active form 1α,25 dihydroxyvitamin-D3 mediates its cellular functions by binding to VDR. Active VDR forms heterodimers with partner RXR (retinoid X receptor) to execute its physiological actions. HVDRR (Hereditary Vitamin D-Resistant Rickets) is a rare genetic disorder that occurs because of generalized resistance to the 1α,25(OH)2D3. HVDRR is caused by the polymorphic variations in VDR gene leading to defective intestinal calcium absorption and mineralization of newly forming bones. Using point and deletion SNPs of VDR we have studied several HVDRR-associated SNP variants for their subcellular dynamics, transcriptional functions, ‘genome bookmarking’, heterodimeric interactions with RXR, and receptor stability. We previously reported that VDR is a ‘mitotic bookmarking factor’ that remains constitutively associated with the mitotic chromatin to inherit ‘transcriptional memory’, however the mechanistic details remained unclear. We document that ‘genome bookmarking’ property by VDR is critically impaired by naturally occurring HVDRR-associated point and deletion variants found in patients. Furthermore, these HVDRR-associated SNP variants of VDR were found to be compromised in transcriptional function, nuclear translocation, protein stability and intermolecular interactions with its heterodimeric partner RXR. Intriguingly, majority of these disease-allied functional defects failed to be rescued by RXR. Our findings suggest that the HVDRR-associated SNP variations influence the normal functioning of the receptor, and this derived understanding may help in the management of disease with precisely designed small molecule modulators.

Vitamin D Receptor (VDR) Genetic Variants: Relationship of FokI Genotypes with VDR Expression and Clinical Disease Activity in Systemic Lupus Erythematosus Patients.

Vitamin D (VD) deficiency is more frequent in systemic lupus erythematosus (SLE) patients than in control subjects (CS); genetic variants in the VD receptor (VDR) could contribute to the clinical disease activity. This study was aimed to determine the association of the VDR variants FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) with susceptibility to the disease, VD status, VDR mRNA expression, and clinical disease activity in SLE patients. A cross-sectional study was conducted in 194 SLE and 196 CS Mexican women. Immunoassays quantified serum calcidiol and calcitriol. Genotyping was performed by allelic discrimination assays and mRNA VDR expression by qPCR. The FokI variant was not in linkage disequilibrium with BsmI, ApaI, and TaqI&nbsp;VDR variants. SLE patient carriers of the TT FokI genotype showed higher clinical disease activity scores. Notably, the mRNA VDR expression was higher in SLE patients vs. CS, in active vs. inactive SLE patients, and in participants of both study groups with vitamin D deficiency, higher calcitriol levels, and TT FokI genotype carriers. In conclusion, the TT FokI VDR genotype was related to high VDR expression and clinical disease activity in systemic lupus erythematosus patients.

ASSOCIATION OF VITAMIN D RECEPTOR (VDR) VARIANTS, HYDROXYUREA THERAPY, AND CEREBROVASCULAR DISEASE STATUS ON 25-HYDROXYVITAMIN D (25(OH)D) LEVELS IN PATIENTS WITH SICKLE CELL ANEMIA

Vitamin D, through binding to its specific receptor, vitamin D receptor (VDR), executes actions beyond calcium metabolism and impacts sickle cell anemia (SCA) pathophysiology, such as regulating inflammation, vascular tone, and thrombogenesis. Genetic polymorphisms that can potentially disturb VDR function or its levels may modify the vitamin D mechanism and have already been associated with several conditions, including stroke. Therefore, we evaluated the association of 25-hydroxyvitamin D (25(OH)D) levels with VDR gene polymorphisms, hydroxyurea (HU) therapy, and cerebrovascular disease (CVD) in an SCA cohort. 25(OH)D levels were determined using the automated microparticle chemiluminescence method in 45 non-related SCA patients (55.5% males). Genotyping for functional FokI (rs2228570) and Cdx-2 (rs11568820) VDR polymorphisms was performed with TaqMan fluorogenic probes. Nonparametric Mann-Whitney and Kruskal-Wallis tests, followed by Dunn's multiple comparisons post-test, were used to analyze continuous variables. The median 25(OH)D levels were 20.9 ng/mL (range, 10 – 37.2 ng/mL). 18 patients (40%) had vitamin D deficiency (25(OH)D < 20ng/mL), 22 (49%) had insufficient levels (25(OH)D 20 - 30 ng/mL) and 05 (11 %) had sufficient levels (25(OH)D > 30 ng/mL). No difference was observed in 25(OH)D levels according to FokI and Cdx-2 genotypes (p > 0.05). However, 25(OH)D levels were decreased in patients with CVD (p = 0.026) and patients under hydroxyurea (HU) therapy (p = 0.005). Considering patients under HU therapy, individuals with variant TT- FokI genotype had lower levels of 25(OH)D (median: 13.9 ng/mL) when compared to those with CC/CT genotypes (median: 20.2 ng/mL; p = 0.03). In the group of individuals without HU therapy, this finding was not observed (p > 0.05). Although not statistically significant, patients with CVD and TT- FokI genotype had lower levels of 25(OH)D (median: 12.3 ng/mL) when compared to individuals with CC/CT genotypes (median: 20,8 ng/mL; p = 0.075). Despite the influence of HU in 25(OH)D levels has already been addressed with conflicting results, the mechanism that might explain these associations is not yet known. Moreover, previous findings indicate that the effect of functional VDR variants can be influenced by vitamin D status. Therefore, under the influence of factors that affect vitamin D levels, the defective VDR isoform, resulting from the FokI polymorphism, possibly accentuates the 25(OH)D deficiency, contributing to an adverse outcome. In summary, 25(OH)D levels are reduced in SCA patients with CVD and those under HU therapy. Further studies are required to determine the mechanism underlying HU and 25(OH)D levels associations and the effect of vitamin D supplementations in patients with CVD in SCA, especially those under HU therapy.

VDBP and VDR Mutations May Cause In-Stent Restenosis

Objective: In-stent restenosis (ISR) is the narrowing of a stented coronary artery lesion. A considerable number of patients undergoing percutaneous coronary intervention (PCI) are affected by ISR. The predominant mechanism in the development of ISR is an inflammatory response to vessel wall injury during PCI. Vitamin D is reported to have anti-inflammatory properties, so it may also be related with ISR. Therefore, in this study the relationship between vitamin D receptor (VDR), vitamin D binding protein (VDBP) gene variations and ISR were investigated. &#x0D; Methods: Fifty-eight ISR patients who have chest pain, underwent angiography and were found to have restenosis in the previously inserted stent were included in the patient group and thirty-five patients who have chest pain and were not found to have restenosis in their previous stent in coronary angiography were included in the control group. rs7041 and rs4588 variations in VDBP; rs1544410 and rs2228570 variations in VDR were investigated by real-time polymerase chain reaction (RT-PCR). Results were evaluated statistically. &#x0D; Results: The CC genotype of rs2228570 variation of VDR and the CA genotype of rs4588 variation of VDBP were found statistically high in patient group. rs7041 variation was found statistically high in patients who had myocardial infarction history before stent implantation. Additionally, it was demonstrated that vitamin D deficiency (vitamin D level

Genetic variations of vitamin D receptor and vitamin D supplementation interaction in relation to serum vitamin D and metabolic traits: a systematic review and meta-analysis.

Background: It is now becoming increasingly recognized that the effects of vitamin D supplementation may vary by several factors including vitamin D deficiency status, ethnicity, and/or the presence of genetic variants, which affect individual responses to supplementation. This study investigates the interaction between metabolic traits and circulating 25-hydroxyvitamin-D (25OHD) concentration with 4 polymorphisms of vitamin D receptor (VDR) including BsmI, ApaI, TaqI, FokI, and vitamin D supplementation. Methods: A systematic review and meta-analysis of papers until August 2021 on PubMed, The Cochrane Library, Scopus, Web of Science, Google Scholar, ProQuest, Science Direct, and Embase about the association between functionally relevant VDR variants and vitamin D supplementation on circulating 25OHD and metabolic traits. Results: A total of 2994 cases from 16 randomized controlled trial (RCT) studies were included in meta-analyses. There were no significant changes in the serum concentrations of 25OHD and metabolic traits after vitamin D supplementation in different variants of BsmI, ApaI, TaqI, and FokI polymorphism in the VDR gene in the overall analysis (p>0.05). However, the results showed there is significant interaction between these above VDR polymorphisms and vitamin D supplement on serum 25OHD level after subgroup analyses based on the study duration, gender, age, BMI, health status, Hardy-Weinberg Equilibrium, PCR, and race (p<0.05). Conclusions: The present meta-analysis demonstrates that the effect of vitamin D supplementation on serum 25OHD and metabolic traits is independent of genetic variants of the VDR gene (BsmI, ApaI, TaqI, and FokI). However, future trials should consider inter-individual differences and, in particular, should aim to clarify whether certain subgroups of individuals may benefit from vitamin D supplementation in the context of metabolic health.

Vitamin D Analogs Bearing C-20 Modifications Stabilize the Agonistic Conformation of Non-Responsive Vitamin D Receptor Variants

The Vitamin D receptor (VDR) plays a key role in calcium homeostasis, as well as in cell proliferation and differentiation. Among the large number of VDR ligands that have been developed, we have previously shown that BXL-62 and Gemini-72, two C-20-modified vitamin D analogs are highly potent VDR agonists. In this study, we show that both VDR ligands restore the transcriptional activities of VDR variants unresponsive to the natural ligand and identified in patients with rickets. The elucidated mechanisms of action underlying the activities of these C-20-modified analogs emphasize the mutual adaptation of the ligand and the VDR ligand-binding pocket.

Vitamin D receptor gene polymorphisms in chronic kidney disease Egyptian children: effect on biochemical markers of bone mineral disorders.

The aim of this study was to assess the association between four vitamin D receptor (VDR) single nucleotide polymorphisms BsmI (rs1544410), ApaI (rs7975232), FokI (rs2228570) and TaqI (rs731236) and the susceptibility to chronic kidney disease (CKD) in Egyptian children and to evaluate their association with mineral status in these patients. The current study included 305 patients with CKD and 100 apparently healthy children. We measured the serum vitamin D (VD), para-thyroid hormone (PTH) level and fibroblast growth factor 23 (FGF-23) levels by ELISA method. The genotyping of the four VDR gene variants was carried out by PCR-RFLP technique. The TaqI AG &amp; the BsmI TT genotypes were associated with a significantly higher risk of CKD. The expression of 25-OH D serum level was decreased in patients with TaqI GG &amp; AG genotypes groups and in patients with BsmI TT genotype group The expression of PTH serum level was increased in patients with BsmI CT genotype group. The expression of FGF-23 serum level was increased in patients with Taq1 AG genotype group. We found 3 specific haplotypes; AGCA, AGCC and GGCA for healthy controls. Our study showed an association between VDR TaqI, BsmI polymorphisms and the susceptibility to CKD. The existence of VDR vari-ants affected the protein expression of VD, FGF-23 and PTH. The AGCA, AGCC and GGCA haplotypes were considered as protec-tive factors against the development of renal nephropathy in our population.

Association of Vitamin D Receptor Polymorphism (rs2228570, rs1544410, rs7975232, and rs731236) and Macrophage Migration Inhibitory Factor -173 G/C (rs755622) with the Susceptibility of Active Pulmonary Tuberculosis in Makassar, Indonesia

BACKGROUND: The study of Vitamin D Receptor (VDR) and Macrophage Migration Inhibitory Factor (MIF) polymorphisms, associated with active pulmonary tuberculosis (ATB) presents varying results. AIMS: This study aimed to investigate the association between VDR rs2228570, rs1544410, rs7975232, rs731236 and MIF -173 G/C (rs755622) single nucleotide polymorphism (SNP), with susceptibility of developing ATB, and positivity of Interferon Gamma Release Assay (IGRA) results (in household contact). METHODS AND MATERIAL: This study involved 83 ATB and 73 household contacts in Makassar. We checked IGRA based on ELISA in household contacts by using QuantiFERON TB Gold Plus test, and we found that 61.64% (n = 45) of household contacts had positive IGRA. Polymorphism examination was carried out by Sanger sequencing. RESULTS: VDR rs2228570 T/T and T/C-T/T were significantly associated with higher risk of active tuberculosis. VDR rs7975232 G/G genotype was associated with an increased risk of developing active TB compared to T/T-T/G. Haplotype analysis of VDR rs2228570, rs1544410, rs7975232, rs731236 and combination with MIF rs755622 demonstrated that TGGTG was observed to have a higher risk of tuberculosis. CONCLUSIONS: The combination of VDR and MIF variants may contribute to the susceptibility of active tuberculosis disease.

Polymorphisms of Vitamin D Receptor and the Effect on Metabolic and Endocrine Abnormalities in Polycystic Ovary Syndrome: A Review.

Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorder in women of reproductive age. Vitamin D and its receptor are thought to play an important role in PCOS susceptibility, although the impact of vitamin D receptor (VDR) polymorphisms on the hormonal and metabolic profile is still controversial. A literature search in PubMed and Embase was performed up to September 2020 for case-control studies in women suffering from PCOS, with outcome related to VDR polymorphisms effect on metabolic/endocrine disturbances. We have found 16 eligible studies including 2566 women with PCOS and 2430 controls. ApaI polymorphism seemed to be associated with hyperandrogenism in both Asian and Caucasian population. FokI variant was correlated with metabolic/endocrine parameters especially in Asian population, while a relation between Cdx2 genotypes and insulin sensitivity was observed in both ethnicities. VDR polymorphisms have an important role in PCOS development and related hormonal and metabolic abnormalities. Few case-control studies analysed the interaction between VDR variants and metabolic/endocrine parameters with the majority of the articles focused on the Asian region. Further research on various ethnic populations with larger sample size are still needed for a definitive conclusion, in order to allow early diagnosis and prevention of PCOS comorbidities.

Vitamin D Level and Vitamin D Receptor Genetic Variation Were Involved in the Risk of Non-Alcoholic Fatty Liver Disease: A Case-Control Study.

BackgroundIt has been demonstrated that vitamin D receptor (VDR), a key gene in the metabolism of vitamin D (VD), may affect the development of Non-alcoholic fatty liver disease (NAFLD) by regulating VD level and its biological effects.ObjectivesTo investigate the effects of serum VD level, VDR variation, and a combination of VDR SNP and environmental behavior factor on the risk of NAFLD.MethodsA total of 3023 subjects from a community in Nanjing were enrolled, including 1120 NAFLD cases and 1903 controls. Serum 25(OH)D3 levels were measured and eight single nucleotide polymorphisms (SNPs) in VDR gene were genotyped.ResultsLogistic regression analyses indicated that VD sufficiency and VD insufficiency were significantly associated with a low risk of NAFLD (all P<0.05; all P trend <0.05, in a locus-dosage manner). After adjusting for gender and age, VDR rs2228570-A and rs11168287-A alleles were all reduced the risk of NAFLD (all P FDR=0.136, in dominant model; P trend =0.039, combined effects in a locus-dosage manner). The protective effects of two favorable alleles were more evident among subjects ≤40 years, non-hypertension, non-hyperglycemia and non-low high density lipoprotein-cholesterol (all P<0.05). The area under the receiver operating curve of the combination of VDR SNP and exercise time for assessing NAFLD risk was slightly higher than that of only including exercise time or neither (all P<0.05).ConclusionHigh serum VD levels and VDR variants (rs2228570-A and rs11168287-A) might contribute to a low risk of NAFLD in Chinese Han population. The inclusion of VDR SNP and exercise time could improve the efficiency in assessment of NAFLD risk, which might provide a novel perspective for early screening and preventing NAFLD.