Vitamin D Receptor Polymorphisms Research Articles

Effects of VDR and CYP24A1 gene polymorphisms on the outcome of supraglottic larynx cancer.

Vitamin D has been demonstrated to play a protective role in carcinogenesis. Polymorphisms of the vitamin D receptor (VDR) genes and 24-α-hydroxylase (encoded by CYP24A1) may affect the outcome of some cancers. This study examines the effects of the VDR gene and CYP24A1 single nucleotide polymorphisms on the outcome of supraglottic larynx cancer. Patients diagnosed with supraglottic larynx cancer between 2017 and 2022 were enrolled. Single nucleotide polymorphisms of the VDR gene (rs2228570, rs731236, rs7975232, rs11574113, rs11168267 and rs11168266) and CYP24A1 gene (rs4809960, rs6022999, rs6068816, rs2259735 and rs2296241) were investigated. All patients were followed up for any evidence of local recurrence, regional recurrence, distant metastasis, and second primary tumor development. Cox regression analysis was performed to evaluate the prognostic value of single-nucleotide polymorphisms (SNPs). Kaplan-Meier method was used for survival analysis. 87 patients were included. The mean follow-up time was 45.02±24.47 months. Cox regression analysis for locoregional recurrence revealed that the hazard ratio of rs731236 GG was 2.098 (95% CI, range: 1.047-4.202, p=0.037). Locoregional recurrence for rs731236 AA, AG, and GG were 38.6%, 23.1%, and 53.3%, respectively. In the presence of rs731236 GG polymorphism, disease-specific survival was significantly shorter (47.63±7.48 months, p=0.015), and disease-free survival (45.71±6.3 months) was significantly shorter (p=0.040). Rates of metastases and second primary tumors were not significantly different between SNPs. This study has demonstrated the possible effects of VDR rs731236 SNP on the locoregional recurrence and prognosis of supraglottic larynx cancer.

Association between Vitamin D Receptor Polymorphism and Susceptibility to Oral Lichen Planus and Oral Squamous Cell Carcinoma.

Oral squamous cell carcinomas (OSCC) comprise 90-95% of oral cancers. Early diagnosis improved the survival rate of OSCC patients to 80-90%. Oral lichen planus (OLP) is a chorionic inflammatory disease with malignancy potential. The vitamin D receptor (VDR) plays a critical role in the pathogenesis of oral cancer. This study aimed to determine the association between VDR rs7975232 (Apa I) polymorphism and potential susceptibility to OLP and OSCC risks. In this prospective case-control study, a total of 120 blood samples were obtained from OSCC patients (n=29), OLP (n=50), and controls (n=40). VDR rs7975232 polymorphism was studied using the Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) method. Statistical analysis was performed with SPSS Version 23 software. Data were expressed as means ± standard deviation (SD). Age, sex, allelic frequency, and genotyping were compared using the chi-square test. A p-value of less than 0.05 was regarded as statistically significant. The disease risk was estimated by Odds ratio (OR) with a 95% confidence interval. A significant age difference was observed between the controls and the OSCC group (p=0.001). A significant difference was observed in Aa and aa genotypes compared with AA between OSCCs and controls. Moreover, dominant (p<0.001), additive (p<0.001), and allelic (p=0.001) models were different between groups. There was a positive association between rs7975232 VDR polymorphism and susceptibility to OSCC. More experimental evidence must reveal the possible association between rs7975232 and the risk of OLP in a larger cohort.

Prevalence of Vitamin D Receptor Genes Polymorphisms in People with Pulmonary Tuberculosis: A Systematic Review and Meta-Analysis.

Polymorphisms in the vitamin D receptor (VDR) play an effective role in the susceptibility of pulmonary tuberculosis (TB). Given the importance of this polymorphism and its association with pulmonary TB, this study aimed to investigate the prevalence of VDR polymorphisms in people with pulmonary TB. The search process was performed from 2009 to 2023 according to PRISMA (Preferred reporting items for systematic reviews and meta-analyses). The strengthening of the reporting of observational studies in epidemiology (STROBE) checklist was used to qualify the articles. The data was entered into STATA version 14 software, then the fixed effects model and the random effects model, effect size (ES), and Q test (P < 0.10) were used for data analysis at a confidence interval level (CI) of 95%. Two-sided statistical tests were considered with α=0.05. In this research, 28 articles were analyzed. Polymorphisms showed a significant relationship with susceptibility to pulmonary TB (P = 0.000), and significant heterogeneity (P = 0.000) was seen between polymorphisms. FokI (95% CI: 0.39-0.46, P = 0.000, ES = 43%), ApaI (95% CI: 0.31-0.48, P = 0.000, ES = 39%) and BsmI (95% CI: 0.24-0.50, P = 0.000, ES = 37%) showed the most frequent gene polymorphisms after TaqI (95% CI: 0.34-0.77, P = 0.000, ES = 56%). ApaI, BsmI, FokI, and TaqI polymorphisms were found in patients suffering from pulmonary TB. Polymorphisms related to the TaqI gene were the most frequent. Controlling and prescribing vitamin D may be needed in these patients.

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.

BMP6 and VDR gene polymorphisms are associated with osteonecrosis in a sickle cell anaemia cohort.

The occurrence and severity of osteonecrosis in sickle cell anaemia (SCA) vary due to risk factors, including genetic modifiers. Bone morphogenetic proteins (BMPs), particularly BMP6, and the vitamin D receptor (VDR) play key roles in cartilage and bone metabolism, making them potential contributors to orthopaedic outcomes in SCA. Here, we evaluated the association of polymorphisms in BMP6 (rs3812163, rs270393 and rs449853) and VDR (FokI rs2228570 and Cdx2 rs11568820) genes with osteonecrosis risk in a Brazilian SCA cohort. A total of 177 unrelated SCA patients were selected. The AA genotype of BMP6 rs3812163 was independently associated with a lower osteonecrosis risk (p = 0.015; odds ratio (OR): 0.38; 95% confidence interval (CI): 0.18-0.83) and with the long-term cumulative incidence of osteonecrosis (p = 0.029; hazard ratio: 0.56, 95% CI: 0.34-0.94). The VDR rs2228570 TT genotype was independently associated with a lower osteonecrosis risk (p = 0.039; OR: 0.14; 95% CI: 0.02-0.90). In summary, our results provide evidence that BMP6 rs3812163 and the VDR rs2228570 might be implicated in osteonecrosis pathophysiology in SCA and might help identify individuals at high risk.

ApaI and Fok1 Variants of Vitamin D Receptor Gene Associated with Metabolic Syndrome Among Jordanian Women.

The association between vitamin D receptor (VDR) polymorphisms and metabolic syndrome (MS) remains debatable. The current study aimed to determine the correlation of VDR gene polymorphisms with MS among Jordanian women. This case-control study enrolled 100 women with MS and 100 age-matched women as control at Al-Hikma Modern Hospital in Jordan between January 2019 and January 2020. The levels of glycated hemoglobin, fasting glucose, triglyceride, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and 25-hydroxy vitamin D (25(OH)D) were determined from serum samples of all participants. DNA was extracted from whole blood samples, and VDR gene polymorphisms Apa1, Taq1, Bsm1, and Fok1 were analyzed by polymerase chain reaction and restriction fragment length polymorphism. There was a significant difference between MS patients and control in terms of body mass index (34.3±3.1 vs. 28.1±2.5), glycated hemoglobin (5.9±1.1 vs. 4.6±1.2), fasting blood glucose (6.4±1.6 vs. 5.2±1.4), and total cholesterol (6.5±1.2 vs. 5.3±1.8). The results also demonstrated a statistical difference in the number of MS patients and control with 25(OH)D deficiency (69.0 vs. 33.0), 25(OH)D insufficiency (25.0 vs. 42.0), and 25(OH)D sufficiency (6.0 vs. 25.0) (p < 0.001). MS was significantly associated with VDR polymorphisms among Apa1 and Fok1 genes. The genotype distribution for CC (47.0% vs. 53.0%; p = 0.002) and CA (37.0% vs. 45.0%; p = 0.001) genotypes among Apa1 VDR polymorphism, as well as among TT genotype (38.0% vs. 20.0%; p = 0.025) among Fok1 VDR gene polymorphism significantly differed between MS patients and healthy individuals. However, no associations were detected among Taq1 and Bsm1 VDR genotypes. VDR gene polymorphism of Apa1 and Fok1 variants may increase the risk of metabolic syndrome among Jordanian women.

Assessment of vitamin D status and vitamin D receptor polymorphism in Egyptian children with Type 1 diabetes

BackgroundThe endocrine system of vitamin D regulates about 3 % of the human genome. Vitamin D exerts its actions via a nuclear vitamin D receptor (VDR) which in turn regulates insulin secretion from the pancreas. VDR gene polymorphisms could have an impact on how autoimmune illnesses like Type 1 diabetes mellitus (T1DM) develop. We aimed to explore the relation between T1DM and VDR gene polymorphisms in Egyptian diabetic children and their siblings. MethodsEnzyme-linked immunosorbent assay was used to quantify 25(OH) vitamin D in the study, which had 179 participants (group 1 = 85 diabetic children, group 2 = 57 siblings of the patients, group 3 = 37 healthy controls). Real-time polymerase chain reaction (RT-PCR) was used to analyze the genotyping of the VDR gene polymorphisms Apa-I (rs7975232), Fok-I (rs2228570), Taq-I (rs731236) and Bsm-I (rs1544410). ResultsThe mean serum 25(OH) vitamin D levels was significantly lower in T1DM patients (14.99 ± 9.24 ng/mL) and siblings (16.31 ± 7.96 ng/mL) compared to the controls (19.48 ± 7.42 ng/mL) (p = 0.031). The genotypes distribution of VDR Fok-I (rs2228570) and Bsm-I (rs1544410) polymorphisms showed a significant difference between patients, siblings and controls as P = 0.001 and 0.026 respectively, while the VDR ApaI and TaqI polymorphisms did not. FokI-A allele frequency was significantly lower in T1DM patients and siblings than in controls (p < 0.001). FokI-AA genotype had a statistical significant higher vitamin D levels than other genotypes with p value of 0.024. ConclusionOur study found that T1DM children had lower vitamin D levels, and VDR FokI and BsmI gene polymorphisms were linked to T1DM in Egyptian children. Determining the relationship between vitamin D levels and VDR polymorphisms, particularly the FokI and other genetic analyses may aid in the early diagnosis of T1DM in children.

Serum 25-Hydroxyvitamin D, Vitamin D Receptor, and Vitamin-D-Binding Protein Gene Polymorphisms and Risk of Dementia Among Older Adults With Prediabetes.

The association between vitamin D and dementia risk in those with prediabetes remains uncertain. We aimed to evaluate the association of serum 25-hydroxyvitamin D (25OHD) with incident dementia among older adults with prediabetes, and examine whether apolipoprotein E (APOE) genotypes, vitamin D receptor (VDR), and vitamin-D-binding protein (VDBP) gene polymorphisms may modify this association. A total of 34237 participants aged ≥60 with prediabetes (HbA1c <6.5% and ≥5.7%) and without dementia at baseline were included from the UK Biobank. Serum 25-hydroxyvitamin D (25OHD) was measured using chemiluminescent immunoassay method. The primary outcome was incident all-cause dementia. Secondary outcomes included incident Alzheimer's disease (AD) and vascular dementia, respectively. The VDR and VDBP gene polymorphisms included single nucleotide polymorphisms of rs7975232, rs1544410, rs2228570, rs731236, and rs7041, rs4588, respectively. During a median follow-up of 11.8 years, 941 (2.7%) participants developed incident all-cause dementia. Overall, serum 25OHD was inversely associated with all-cause dementia (per standard deviation increment, adjusted hazard ratio: 0.82; 95% confidence interval: 0.75, 0.89). Similar trends were found for incident AD and vascular dementia. Furthermore, there was a stronger inverse relationship between serum 25OHD and all-cause dementia among VDR rs7975232 C allele noncarriers (p-interaction < 0.05). However, APOE Ɛ4, other VDR, and VDBP gene polymorphisms did not significantly modify the relation of serum 25OHD with incident all-cause dementia (all p-interactions >.05). There was an inverse association between serum 25OHD and incident dementia among older adults with prediabetes, especially in VDR rs7975232 AA allele carriers.

Vitamin D receptor (VDR) variants are risk factors for ovarian cancer: a meta-analysis and trial sequential analysis

The importance of Vitamin D in ovarian cancer (OC) has been well documented, and lower levels have been associated with susceptibility to OC. Vitamin D exerts its effect through the vitamin D receptor (VDR). Common genetic variants in the VDR gene (Fok I, TaqI, BamI and ApaI) have been linked with the susceptibility to the development of OC; however, the reports remain contradictory. To draw a valid conclusion, we performed a meta-analysis of the earlier published reports in the present study. The literature search was performed in PubMed, Google Scholar, and Scopus databases. All relevant articles were screened, and eligible reports were identified based on prefixed inclusion and exclusion criteria. Data such as author’s details, year of publication, ethnicity, genotype and allele prevalence in cases and controls were extracted from the eligible reports. The meta-analysis was performed using Comprehensive Meta-analysis Software (CMA) V3. Eight articles, including data from fourteen independent cohorts, comprised 4276 cases and 6739 healthy controls considered for the analysis. VDR FokI and BamI variants revealed a significant association with an increased risk of OC. Other VDR polymorphisms (TaqI and ApaI) failed to demonstrate such an association with OC. Interestingly, the sensitivity analysis revealed minimal deviation from the parent meta-analysis, supporting the robustness of the present analysis. The trial sequential analysis revealed the inclusion of a sufficient number of studies for FokI polymorphism. It highlighted the requirement for additional case-control studies in VDR (ApaI, BamI and TaqI) to draw a definitive conclusion. FokI and BamI polymorphisms are associated with susceptibility to OC.

Vitamin D and Vitamin D Receptor FokI, ApaI, and BsmI Gene Polymorphisms and their Relation with the Risk of Breast Carcinoma: A Case-control Study

Introduction: Breast cancer stands as the leading cause of mortality among women in developing nations. The potential role of Vitamin D in mitigating the incidence of breast cancer is thought to stem from its ability to impede cell proliferation by interacting with the Vitamin D Receptor (VDR). The VDR gene is responsible for encoding the VDR, which plays a pivotal role in mediating the effects of vitamin D. Aim: To analyse vitamin D levels and the association of VDR FokI, ApaI, and BsmI genotypic distribution frequency with the risk of breast cancer. Materials and Methods: The case-control study included 220 samples, including 110 breast cancer patients and 110 agematched control women aged 30-70 years. The Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) genotyping was performed using Deoxyribonucleic acid (DNA) extracted from blood, and the circulating levels of 25-hydroxyvitamin D by case/control were estimated by chemiluminescence immunoassay. Results: The 3’ VDR polymorphism BsmI sequence showed minimal association with breast cancer risk. The bb genotype had a significantly lower odds ratio of 0.056 (p-value&lt;0.05). Conversely, the BB and Bb genotypes exhibited no statistically significant associations with odds ratios of 1.76 (95% CI: 0.36-8.54; p-value&gt;0.05) and 1.30 (95% CI: 0.27- 6.25; p-value&gt;0.05), respectively. Isolated analysis of the FokI variant revealed a significant association with increased breast cancer risk, with odds ratios of 5.49 (FF) and 6.00 (Ff), both demonstrating statistical significance (p-value&lt;0.05), and a Chi-square value of 0.006. Additionally, the p-value for serum Vitamin D levels was found to be highly significant at p-value&lt;0.001, indicating that the levels were significantly lower in individuals newly diagnosed with breast cancer compared to those in the healthy control group. Conclusion: The study found a significant link between breast cancer susceptibility and VDR (FokI) polymorphism FF and Ff genotypes, with minimal impact observed for (BsmI) polymorphism bb genotype. This implies that certain genetic variations, especially in the FokI polymorphism of the VDR gene, are associated with an elevated risk of breast cancer.

Frequency of Healthy Control Genotype of VDR Gene Polymorphisms in the Saudi Population of the Ha'il Region: A Comparative Study with Worldwide Population.

Genetic polymorphisms in the vitamin D receptor (VDR) may influence the biological effects of vitamin D and increase a person's susceptibility to cancer. Previous studies have shown that different ethnic groups exhibit varying frequencies of the VDR gene variants TaqI, ApaI, FokI, and BsmI. However, the allelic distribution of these VDR polymorphisms in the Saudi population of Ha'il region is not sufficiently explored. In this study, efforts were made to ascertain the frequency of VDR polymorphisms in the Saudi population of Ha'il region, and then comparison was made for VDR polymorphism rates with other populations of the world. Allele and genotype frequencies of VDR TaqI, ApaI, BsmI and FokI gene was determined. The frequency distribution for the variant allele of VDR TaqI, ApaI, BsmI and FokI was found to be 70, 33, 50 and 25%, respectively. A significant frequency distribution was found for VDR-TaqI, ApaI and FokI variants in comparison with other populations of the world. Whereas, almost all of the studies dealing with VDR-FokI failed to show substantial difference while comparing with the data reported from the population of Ha'il region of Saudi Arabia. A significant pattern in the frequency of VDR gene variations have been found in the Saudi population of Ha'il region, which may be attributed to ethnic variance. The understanding of the worldwide distribution of VDR markers could help with high-risk screening of those who are exposed to environmental hazards and people of Ha'il region, who are predispose to cancer.

Vitamin D receptor rs3782905 and vitamin D binding protein rs7041 polymorphisms are associated with hepatocellular carcinoma susceptibility in cirrhotic HCV patients

BackgroundThe severity of chronic hepatitis C and susceptibility to hepatocellular carcinoma (HCC) are associated with genetic variations within vitamin D receptor (VDR) in several populations. This study aims to determine the significance of the VDRs (rs2228570, rs3782905, rs11568820) and DBP (rs7041) for the susceptibility to HCC in Egyptian patients with chronic HCV infection and their effect on the progression of liver cirrhosis to carcinogenesis.MethodsSingle nucleotide polymorphisms (SNPs) VDR (rs2228570, rs3782905), and DBP rs7041 were genotyped using restriction fragment length-PCR (RFLP-PCR) technique and VDR rs11568820 was genotyped using single strand polymorphism PCR (SSP PCR). These SNPs genotypes, haplotypes and linkage disequilibrium analyses were examined in 299 Egyptian individuals (100 HCV-cirrhotic patients, 99 HCC- HCV patients, and 100 healthy controls).ResultThe VDR rs2228570 CC genotype, VDR rs3782905 GC and CC genotypes, and DBP rs7041 GG genotype are significantly higher in HCC. It is noteworthy that, VDR rs3782905 CC and DBP rs7041 TG genotypes are higher in HCV induced liver cirrhosis than with HCC progression in HCV infected patients. Furthermore, among patients, the relationship between these SNPs and smoking status, gender, and HCC susceptibility was reported.ConclusionAmong the four investigated SNPs, there are associations between VDR rs3782905 and DBP rs7041 and the HCC progression in Egyptian patients chronically infected with HCV. These SNPs are considered as risk factors in HCV induced liver cirrhosis and HCC. The combinations of these SNPs with smoking status and gender are statistically linked to a high risk of HCC. Future research with a larger sample size of subjects with HCV infection is advised, because chronic liver disease induced by HCV infection is the primary cause of HCC in Egypt. We recommend screening of these SNPs for prediction of LC and HCC development in HCV infected patients, which may improve the used therapeutic protocol. These results suggest that VDR polymorphisms may be potential determinants for HCC susceptibility in Egyptian HCV patients.

Modulation of the vitamin D/vitamin D receptor system in osteoporosis pathogenesis: insights and therapeutic approaches.

Osteoporosis is a prevalent bone disorder characterized by low bone mineral density (BMD) and deteriorated bone microarchitecture, leading to an increased risk of fractures. Vitamin D (VD), an essential nutrient for skeletal health, plays a vital role in maintaining bone homeostasis. The biological effects of VD are primarily mediated through the vitamin D receptor (VDR), a nuclear receptor that regulates the transcription of target genes involved in calcium and phosphate metabolism, bone mineralization, and bone remodeling. In this review article, we conduct a thorough literature search of the PubMed and EMBASE databases, spanning from January 2000 to September 2023. Utilizing the keywords "vitamin D," "vitamin D receptor," "osteoporosis," and "therapy," we aim to provide an exhaustive overview of the role of the VD/VDR system in osteoporosis pathogenesis, highlighting the most recent findings in this field. We explore the molecular mechanisms underlying VDR's effects on bone cells, including osteoblasts and osteoclasts, and discuss the impact of VDR polymorphisms on BMD and fracture risk. Additionally, we examine the interplay between VDR and other factors, such as hormonal regulation, genetic variants, and epigenetic modifications, that contribute to osteoporosis susceptibility. The therapeutic implications of targeting the VDR pathway for osteoporosis management are also discussed. By bringing together these diverse aspects, this review enhances our understanding of the VD/VDR system's critical role in the pathogenesis of osteoporosis and highlights its significance as a potential therapeutic target.

The association between body mass index elevation and differentiation in vitamin D receptor gene expression, genetic polymorphism, and oxidative stress in adult Egyptian individuals

Vitamin D plays a central role in maintaining calcium, phosphorus, and bone homeostasis in close interaction with the parathyroid hormone. Obesity is a significant health problem worldwide, particularly in developed nations. The current study was carried out to investigate the possible relationship between body mass index (BMI) elevation and differentiation in 25-hydroxyvitamin D (VD), vitamin D receptor (VDR) gene expression, and genetic polymorphism besides oxidative stress in adult Egyptian individuals. This was done to explore the mechanisms underlying the suggested role of the VD/VDR complex in the pathogenesis of obesity. A total of 70 subjects (30 obese, 25 overweight, and 15 normal, age: 20–50 years, without other chronic diseases) were selected. The study focused on the determination of VD, VDR gene polymorphism, VDR gene expression, alkaline phosphatase, calcium, phosphorus, glucose, lipid profile, oxidative stress including, oxidant (malondialdehyde), and anti-oxidants (reduced glutathione and superoxide dismutase). The results showed that elevation in BMI led to the percentage of the Ff 'allele' becoming predominant, while the percentage of the FF 'allele' was in the normal BMI range. Also, BMI elevation caused significant reductions in VD and VDR expression, with significant elevations in alkaline phosphatase and the levels of calcium and phosphate in serum. Also, oxidative stress increases with increasing BMI. Elevation in BMI causes a reduction in VD concentration and VDR gene expression levels. Also, the percentage of heterozygous mutant genotype Ff 'allele' is predominantly in the obese human, in contrast to normal subjects, where the percentage of homozygous wild genotype FF 'allele' is predominant. In general, the genetic expression and polymorphism of VD and VDR can be used as a genetic marker for predisposition, diagnosis, prognosis, and progression of obesity.

Cardiovascular and microvascular outcomes according to vitamin D level and genetic variants among individuals with prediabetes: a prospective study

BackgroundWhether serum vitamin D mediate vascular diseases in prediabetic populations remains unclear. This study aimed to determine the associations between circulating 25-hydroxyvitamin D [25(OH)D] levels and vitamin D receptor (VDR) polymorphisms with the risk of macrovascular complications, including myocardial infarction and stroke, and microvascular complications such as diabetic nephropathy and retinopathy, among adults with prediabetes.MethodsParticipants with prediabetes in UK Biobank were included (N = 56,387). Multivariable dose–response and Cox proportion models were used to explore the relationship of serum 25(OH)D status and the risks of vascular complications. The interaction of VDR polymorphisms with serum 25(OH)D level on risks of vascular events was also assessed.ResultsDuring a median follow-up of 12 years, higher levels of 25(OH)D were significantly and nonlinearly associated with a lower risk of macrovascular diseases among prediabetic individuals. The adjusted hazard ratios (95% confidential interval) of serum 25(OH)D levels of ≥ 75.0 nmol/L versus < 25 nmol/L were 0.75 (0.63–0.88) for myocardial infarction, 0.74 (0.55–1.00) for stroke, 1.02 (0.60–1.74) for diabetic nephropathy, and 1.30 (0.92–1.84) for diabetic retinopathy, respectively. The rs2228570 (FokI) polymorphisms significantly interacted with 25(OH)D on incident myocardial infarction (P-interaction = 0.042) and stroke (P-interaction = 0.033). The individuals with serum 25(OH)D level of 50.0–74.9 nmol/L and rs2228570 (FokI) homozygotes had the lowest risks of vascular complications.ConclusionsLower serum 25(OH)D levels are significantly and nonlinearly associated with an increased risk of cardiocerebrovascular diseases in prediabetic individuals, with VDR polymorphisms of rs2228570 (FokI) modify such associations. Monitoring a safe 25(OH)D concentration is suggested to prevent the vascular complications for prediabetes.

Association of Single Nucleotide Polymorphism in VDR, GC Globulin and CYP2R1 with the Risk of Esophageal Cancer.

The proactive role of vitamin D has been well determined in different cancers. The protein that encodes the components of the vitamin D metabolism could appear to play a pivotal role in vitamin D stability and its maintenance. A polymorphism in vitamin-D-receptor (VDR), carrier globulin/binding protein (GC) and cytochrome P-450 family 2, subfamily R, polypeptide 1 (CYP2R1) genes has been predicted to be associated with the development of cancer. This study was designed to detect the association of VDR, GC Globulin and CYP2R1 gene polymorphism with the risk of esophageal cancer in the North-east Indian population. To carry out the study, a total of 100 patients diagnosed with esophageal cancer and 101 healthy controls were enrolled. In a case-control manner, all samples were subjected to do genotype testing for known SNPs on the VDR (rs1544410), GC (rs4588), and CYP2R1 (rs10741657) genes using Restriction-fragment length polymorphism (RFLP) followed by Sanger sequencing. The collected demographic and clinical data were analysed using the statistical software package SPSS v22.0. The VDR haplotype heterozygous TC was found strongly associated with the carcinoma group (OR:1.09, 95%CI:0.67-1.75). The risk factors analysis using the GC globulin rs4588 phenotype, found a positive correlation in terms of mutant AA's harmful influence on the cancer cohort (OR = 1.125, OR=1.125, 95% CI, 0.573-2.206). The influence of the CYP2R1 rs10741657 polymorphism on the malignant cohort revealed that the GG mutant had a significant negative influence on the carcinoma, has an influential role in disease severity ( OR:1.736, at 95% CI; 0.368-8.180). In conclusion, this study revealed the potential association of VDR gene polymorphism in the progression and development of esophageal cancer in north east Indian population cohort.

A Case-Control Study of the Fokl Polymorphism of the Vitamin D Receptor Gene in Bulgarians With Lumbar Disc Herniation.

The present study investigates whether vitamin D receptor (VDR) gene polymorphisms play a role in intervertebral disc degeneration (IDD), a common cause of low back pain (LBP) and reduced quality of life. Specifically, we examined the FokI VDR polymorphism and its potential association with lumbar disc herniation (LDH) in patients from Bulgaria. Previous studies have suggested a link between mutations in the VDR gene and IDD. We investigated whether a potential connection between VDR polymorphisms and LDH was present by comparing the FokI polymorphism of 60 selected patients (25 to 60) with LDH and 60 healthy volunteers within the same age range. We used polymerase chain reaction to assess the phenotype of the examined subjects and statistical tests to evaluate whether the obtained results were statistically significant. The performed genetic and statistical analyses reviewed significant differences in genotypic frequencies between the patient group and healthy volunteers. The frequency of the F allele is notably higher in patients with LDH (80%) compared to volunteers (52%), while the fallele is more common among patients (86.6%) than volunteers (100%). This study strongly suggests that expression of the F allele of the VDR gene may increase the susceptibility of developing LDH, while having the f allele could potentially have a protective effect. Our results shed light on the underlying complex mechanisms contributing to the development of LDH.

Altered Vitamin D Receptor Expression in Apa-I (rs7975232) Allelic Variants-A Probable Risk Factor for Susceptibility to Hepatitis B Virus Infection and Disease Progression.

Vitamin D exerts its antiviral effect through vitamin D receptor (VDR)/retinoid X receptor-mediated host immunomodulation. Besides the downregulation of VDR expression, its polymorphism was also observed among hepatitis B virus (HBV)-positive patients. To understand the possible link between VDR polymorphism and its altered expression during HBV infection and disease progression, VDR Apa-I [rs7975232 (C>A)] single nucleotide polymorphism (SNP) was analyzed in a case-control manner. VDR Apa-I (rs7975232, C>A) polymorphism was studied using 340 HBV patients and 102 healthy controls. Genotype analysis and gene expression study was performed using restriction fragment length polymorphism and quantitative polymerase chain reaction, respectively. Statistical analysis was performed using SPSS (IBM) considering p-value <0.05 as significant for comparing the differences between the groups. Significant mean difference in VDR expression was observed between HBV-positive patients (1.6 ± 0.94) and controls (0.69 ± 0.73). Furthermore, the mean fold change of Healthy control with CC genotype (1.92 ± 0.99) was found to be marginally significant compared with mutant genotype (CA/AA) (1.08 ± 0.43/0.59 ± 0.56, p = 0.045). In HBV+ patients, the mean fold change in the CC genotype was 0.88 ± 0.38, which exhibits a significant mean difference upon comparison with other genotypes (0.52 ± 0.49, 0.113 ± 0.34; p = 0.018, p = 0.048). However, the fold change value does not differ between CA and AA genotypes. Further comparative analysis of VDR expression between the control and case also exhibits significant differences (p = 0.001) among allelic variants. Observed genotype distribution frequency exhibits a significant association with disease type. The mutant genotype was found to be significantly associated with HBV infection and disease progression, (odds ratio = 0.730, 95% confidence interval = 0.462-1.152, p = 0.06). VDR SNP rs7975232 (C>A) may affect VDR expression by controlling several other variables and suggest that deviation from wild-type genotype (CC) is associated with downregulation of expression, which in turn involved in host immunomodulation in favor of HBV infection and disease progression.

Vitamin-d receptor (VDR) polymorphism and types of HBV related liver disease along with an SVM based disease prediction model

BackgroundPolymorphism in genes associated with Vitamin-D metabolism and its receptor molecule altogether modulates the level of active serum Vitamin-D level and as such serves as potent immune modulator. Impact of this polymorphism on outcome of HBV related liver disease is poorly understood till date. This study focus on analysing the VDR polymorphism (TaqI, ApaI, and BsmI) and its associated molecules GC-Globulin and CYP2R1 among HBV infected patients and its probable correlation with disease progression. Method and resultsThree hundred forty HBV infected patients belonging to three distinct clinical groups, Acute Viral hepatitis (AVH, n = 205), Chronic Hepatitis (CH, n = 84) and hepatocellular carcinoma (HCC, n = 51) along with 102 healthy control were included in the study. VDR, GC and CYP2R1 polymorphism were genotyped by PCR-RFLP method followed by Sanger sequencing. Haplotype distribution was analyzed using SHEsis software. Logistic regression analysis was performed to find the association between different genotype and VDR haplotype with progression of liver disease. Further, an SVM based prediction model has also been described in detection of different disease stage. ConclusionApa-I CC genotype was more frequently observed among chronic HBV patients and HCC than the acute cases among North east Indian population (OR = 2.241, C·I = 0.504–5.558. p = 0.001). The occurrence of bAt haplotype was also found to be significantly higher among Chronic (p = 0.004) and HCC (p = 0.001 < 0.05) cases in comparison to acute cases. Further, logistic regression analysis after adjusting covariates like age, gender, serum AST/ALT level, serum albumin and platelet count, showed that Apa-I CC genotype and bAt haplotype were independent predictors for advancement of acute to chronic HBV infection and further. The SVM based prediction model using similar covariates also predicts the different disease stage with 90% accuracy.

Genetic susceptibility of vitamin D receptor gene polymorphisms on autosomal recessive primary microcephaly patients in Pakistani population: a case-control and in-silico study.

Autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder that leads to reduced cerebral cortex caused by a mutation in corticogenesis. The expression of the Vitamin D receptor (VDR) gene is involved in the proliferation and differentiation of neural stem cells, and VDR polymorphisms have been associated with various neurological disorders. However, their relationship with MCPH has not been explored. This study aimed to investigate the association of VDR polymorphisms with MCPH due to its role in Wnt signaling pathway and its In-silico analysis. Blood samples of 64 MCPH patients and 52 controls were collected to genotype VDR SNPs (TaqI (rs731236), FokI (rs2228570) and BsmI (rs1544410). In-silico tools were also used to assess the effects of exonic SNPs on mRNA and protein structure and pathogenicity of exonic and intronic SNPs. The study found that serum 25-OH vitamin D3 levels were significantly different in MCPH patients and healthy controls (P = 0.000). The genetic analysis showed that VDR polymorphisms of FokI and BsmI were seven times more frequent in MCPH patients than in controls (P < 0.05) and the recessive model for TaqI and dominant model for BsmI polymorphisms were also associated with the pathogenesis of MCPH. In-silico analysis showed that the pathogenicity effects of rs2228570 and rs1544410 are neutral while rs731236 causes a silent mutation which has no effect on VDR protein. VDR polymorphisms of FokI and BsmI are associated with the risk of MCPH. These findings suggest that VDR polymorphisms play a role in MCPH, which could provide important insights for understanding the molecular mechanisms of the disease.