Vitamin D Receptor Single Nucleotide Polymorphisms Research Articles

The Association of Vitamin D Receptor Polymorphisms with COVID-19 Severity.

Association studies of vitamin D receptor (VDR) polymorphisms with COVID-19 severity have produced inconsistent results in different populations. Herein we examined VDR gene polymorphisms in a Caucasian Greek cohort of COVID-19 patients. This was a case-control study in a tertiary university hospital in Greece including 137 COVID-19 patients with varying disease severities and 72 healthy individuals. In total 209 individuals were genotyped for the FokI (rs10735810), ApaI (rs7975232), TaqI (rs731236) and BsmI (rs1544410) single-nucleotide polymorphisms (SNP) of the VDR gene by polymerase chain reaction and restriction fragment length polymorphism analysis (PCR-RFLPs). Statistical analyses were performed to determine the association between genotype and disease severity, adjusting for various confounding factors. Genotype distribution of the studied VDR SNPs in the control group was in Hardy-Weinberg equilibrium. The TaqI variant was differentially distributed between controls and COVID-19 patients according to the additive model (p = 0.009), and the CC genotype was significantly associated with an increased risk for severe COVID-19 according to the recessive model [OR: 2.52, 95%CI:1.2-5.29, p = 0.01]. Multivariate analysis demonstrated a robust association of COVID-19 severity and TaqI polymorphism in the recessive model even after adjusting for multiple confounders, including age, sex and CRP levels [Adj.OR:3.23, 95%CI:1.17-8.86, p = 0.023]. The distribution of FokI, ApaI and BsmI genotypes was similar between COVID-19 patients and controls. The CC genotype of TaqI polymorphism is significantly associated with an increased risk for severe COVID-19 independently of age, sex or degree of inflammation.

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.

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.

The Influence of Single Nucleotide Polymorphisms on Vitamin D Receptor Protein Levels and Function in Chronic Liver Disease.

Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene have been associated with chronic liver disease. We investigated the role of VDR SNPs on VDR protein levels and function in patients with chronic liver disease. VDR expression levels were determined in peripheral T lymphocytes (CD3+VDR+), monocytes (CD14+VDR+), and plasma from patients (n = 66) and healthy controls (n = 38). Genotyping of SNPs and the determination of expression of VDR/vitamin D-related genes were performed by using qPCR. The effect of FokI SNP on vitamin D-binding to VDR was investigated by molecular dynamics simulations. CD14+VDR+ cells were correlated with the MELD score. The ApaI SNP was associated with decreased CD3+VDR+ levels in cirrhotic patients and with higher liver stiffness in HCV patients. The BsmI and TaqI SNPs were associated with increased VDR plasma concentrations in cirrhotic patients and decreased CD14+VDR+ levels in HCV patients. The FokI SNP was associated with increased CD3+VDR+ levels in cirrhotic patients and controls. VDR polymorphisms were significantly related to the expression of genes critical for normal hepatocyte function and immune homeostasis. VDR expression levels were related to the clinical severity of liver disease. VDR SNPs may be related to the progression of chronic liver disease by affecting VDR expression levels.

Association of Vitamin D Receptor Gene Polymorphisms with Cardiometabolic Phenotypes in Hispanics: A Life Course Approach.

The vitamin D receptor (VDR) is vital for maintaining calcium and phosphate balance and regulating bone metabolism. Recent research has suggested that VDR also plays an essential role in metabolic diseases. Previous studies on non-Hispanic whites have shown that VDR single nucleotide polymorphisms (SNP) are associated with cardiometabolic phenotypes. However, the association between VDR SNPs and cardiometabolic traits in Hispanics remains unclear. This study investigated the association between VDR SNPs and cardiometabolic phenotypic data in self-reported Hispanics (n = 1610) from the Arizona Insulin Resistance registry and Sangre Por Salud Biobank. The study population was predominantly female (66.4%) with a mean age of 40 ± 14 years (n = 121 <18 years) and an average body mass index (BMI) of 29.8 ± 6.3 kg/m2. We performed a genotyping association analysis of VDR SNPs (Taq1-rs731236, Fok1-rs2228570 and Apa1-rs7975232) with cardiometabolic traits using linear regression models. The results showed that Taq1 and Apa1 were strongly associated with systolic blood pressure (SBP) in children (<18 years), while Fok1 was associated with measures of adiposity, including fat mass, waist circumference, and BMI. In age-stratified adult (≥18 years) models, Taq1 was strongly associated with hemoglobin A1c, while Apa1 was associated with BMI and fasting glucose. Fok1 had no significant associations in the adult models. In conclusion, the VDR SNPs were associated with several cardiometabolic phenotypes in this Hispanic sample, but the type and strength of the associations varied by age group.

Allelic Discrimination of Vitamin D Receptor Polymorphisms and Risk of Type 2 Diabetes Mellitus: A Case-Controlled Study.

(1) Background: Type 2 diabetes mellitus (T2DM) is one of the rapidly growing healthcare problems, and several vitamin D receptor (VDR) polymorphisms seem to modulate the risk of T2DM. Our research was designed to investigate the allelic discrimination of VDR polymorphisms and T2DM occurrence risk. (2) Methods: This case-control research included 156 patients with T2DM and 145 healthy control subjects. Most of the study population were males 56.6% vs. 62.8% in the case and control groups, respectively. Genotyping for VDR single nucleotide polymorphisms (SNPs), rs228570 (Fok1), rs7975232 (Apa1), and rs1544410 (Bsm1) was compared between both groups. (3) Results: There was a negative link between vitamin D levels and insulin sensitivity. A significant difference was noted in the allelic discrimination of VDR polymorphism rs228570 and rs1544410 between the study groups (p < 0.001). No difference was observed in the allelic discrimination of VDR polymorphism rs7975232 between the groups (p = 0.063). Moreover, T2DM patients had significantly higher levels of fasting blood sugar (FBS), glycated hemoglobin HbA1c, 2-h post-prandial blood sugar (PP), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), total cholesterol, and triglycerides (p < 0.001), while High-Density Lipoprotein (HDL) Cholesterol (HDL-C) was significantly decreased (p = 0.006). (4) Conclusions: VDR polymorphisms had a positive association with T2DM risk among the Egyptian population. Further large-scale research using deep sequencing of samples is strongly urged to investigate different vitamin D gene variants and interactions, as well as the influence of vitamin D on T2DM.

Association of vitamin D receptor polymorphisms with cardiometabolic conditions in Pakistani population.

Apart from bone related effects, vitamin D has roles in immune modulation, hypertension, diabetes and cardiovascular diseases. Metabolic functions of vitamin D are mediated after binding with vitamin D receptor (VDR). VDR polymorphisms affect its physiological functions. Several VDR single nucleotide polymorphisms (SNPs) were reported previously. However, VDR polymorphisms causing influence on cardiovascular and metabolic disorders have not been investigated in the Pakistani population so far. Therefore, the present study was conducted to evaluate the role of VDR polymorphisms (rs2228570 and rs7975232) in the pathobiology of cardiometabolic disorders. In total, 400 cardiometabolic patients and 226 healthy control human adults were enrolled from Faisalabad, Pakistan. Biochemical parameters (serum glucose, liver function test, renal function test and lipid profile) were analyzed by standard kit methods. Genetic analysis was done by ARMS-PCR assay. Data was analyzed in SPSS v20. Regression analysis revealed that GG and AG genotypes of rs2228570 A>G polymorphism significantly increased the risk of hypertension in cardiovascular patients by 5.29 and 5.94 times respectively (GG: OR=5.29, 95% CI=1.63-17.2, p=0.005; AG: OR=5.94, 95% CI=1.70-20.7, p=0.005). However, rs7975232 C>A polymorphism was not correlated with cardiometabolic conditions. In conclusion, GG and AG genotypes of VDR SNP rs2228570 significantly contribute to hypertension in cardiovascular disease patients.

Association of vitamin D levels and polymorphisms in vitamin D receptor with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a leading cause of death. The prevalence of T2DM in countries of the Middle East and North Africa (MENA) region, including Jordan, is among the highest worldwide. The reason(s) behind the epidemic nature of T2DM in Jordan are unknown but warrant further exploration. Studies have indicated that T2DM could be influenced by diet and/or genetic background. Evidence suggests that numerous patients with T2DM are deficient in vitamin D. The activity of vitamin D on its target tissues may be influenced by single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene. It was therefore hypothesized that SNPs in VDR could modify the risk of T2DM. To test this hypothesis, 125 patients with T2DM were recruited along with 125 controls. The study subjects were genotyped for variations in rs2228570, rs1544410, rs7975232, and rs731236 SNPs in the VDR. The levels of 25-hydroxyvitamin D [25(OH)D] were measured from the serum. The analysis revealed that reduced 25(OH)D and age were associated with the risk of T2DM (P<0.05). Moreover, under a dominant inheritance model, the GG genotype of rs2228570 was revealed to increase the risk of T2DM in univariate and multivariate analysis (P<0.05). Additionally, a chromosomal block containing the GAAG haplotype of VDR SNPs increased the risk of T2DM (OR=1.909; CI: 1.260-2.891; P=0.0021). Collectively, the present study revealed that low levels of serum 25(OH)D and rs2228570 of the VDR gene are associated with the risk of T2DM.

Significant association between TaqI and FokI VDR gene polymorphisms and chronic spontaneous urticaria in a Colombian Caribbean population.

Chronic spontaneous urticaria (CSU) is an inflammatory skin disease related to poor quality of life. Previous studies have found that vitamin D deficiency and vitamin D receptor (VDR) TaqI, BsmI, FokI, and ApaI gene single-nucleotide polymorphisms (SNPs) influence immune response and susceptibility to skin disorders. To explore the role of VDR SNPs, and the association of vitamin D serum levels in a sample of Colombian Caribbean CSU patients. Methods: It is a case-control study. A group of CSU patients (n = 100) was compared with healthy individuals as a control group (n = 100). VDR polymorphisms were genotyped by quantitative polymerase chain reaction and Taqman® probes. Allelic, genotypic, and haplotype associations were estimated. Serum vitamin D levels were measured using enzyme-linked-immunosorbent serologic assay. Compared to the control group, the presence of G allele in TaqI and A allele in FokI SNPs of VDR gene was found to be a risk factor for CSU (odds ratio (OR) estimated using logistic regression adjusted by gender: 2.08 and 1.61, respectively, all P values < 0.05). The individuals who carry GCCA haplotype showed decrease in vitamin D levels (11.34 ng/mL; P = 0.002) with the G allele of TaqI and A allele of FokI gene SNPs. We reported for the first time the association of TaqI [rs731236] and FokI [rs2228570] VDR gene SNPs showing as a risk factor for CSU in a sample of multiethnic patients from the Colombian Caribbean population.

Vitamin D Metabolites Are Associated with Physical Performance in Young Healthy Adults.

This study aimed to determine vitamin D metabolites and vitamin D receptor (VDR) single-nucleotide polymorphism (SNP) relationships with physical performance. In 1205 men and 322 women (94.8% White Caucasian, 22.0 ± 2.8 yr) commencing military training, we measured serum vitamin D metabolites (25-hydroxyvitamin D (25(OH)D) and 24,25-dihydroxyvitamin D (24,25(OH) 2 D) by high-performance liquid chromatography tandem mass spectrophotometry and 1,25-dihydroxyvitamin D (1,25(OH) 2 D) by immunoassay), VDR SNPs (rs2228570, rs4516035, and rs7139166 by polymerase chain reaction genotyping), and endurance performance by 2.4-km run, muscle strength by maximal dynamic lift, and muscle power by maximal vertical jump. Serum 25(OH)D was negatively associated with 2.4-km run time and positively associated with muscle power ( β = -12.0 and 90.1), 1,25(OH) 2 D was positively associated with run time and negatively associated with strength and muscle power ( β = 5.6, -1.06, and -38.4), and 24,25(OH) 2 D was negatively associated with run time ( β = -8.9; P < 0.01), after controlling for age, sex, smoking, alcohol, physical activity, time outdoors, season, and body mass index. Vitamin D metabolites (25(OH)D, 1,25(OH) 2 D, and 24,25(OH) 2 D) together explained variances of 5.0% in run time, 0.7% in strength, and 0.9% in muscle power (Δ F P < 0.001). All performance measures were superior with low 1,25(OH) 2 D:24,25(OH) 2 D ratio ( P < 0.05). VDR SNPs were not associated with physical performance (Δ FP ≥ 0.306). Vitamin D metabolites accounted for a small portion of variance in physical performance. Associations between vitamin D metabolites and run time were the most consistent. VDR SNPs explained no variance in performance. Greater conversion of 25(OH)D to 24,25(OH) 2 D, relative to 1,25(OH) 2 D (i.e., low 1,25(OH) 2 D:24,25(OH) 2 D ratio), was favorable for performance, indicating 24,25(OH) 2 D may have a role in optimizing physical performance.

Crosstalk Between Gut Microflora and Vitamin D Receptor SNPs Are Associated with the Risk of Amnestic Mild Cognitive Impairment in a Chinese Elderly Population.

The interactions between environmental factors and genetic variants have been implicated in the pathogenesis of Alzheimer's disease (AD). The altered gut microbiota (GM) and vitamin D deficiency are closely associated with the higher risk of AD. This study was performed to evaluate whether the crosstalk between GM and single nucleotide polymorphisms (SNPs) of vitamin D receptor (VDR) or vitamin D binding protein (VDBP) have a link with the risk of amnestic mild cognitive impairment (aMCI) in the Chinese elderly population. A total of 171 aMCI patients and 261 cognitive normal controls (NC) were enrolled in this study. Six tag SNPs of VDR and VDBP were genotyped by PCR-RFLP. The serum levels of vitamin D, Aβ1-42, and p-tau (181P) were determined by using of ELISA kits. The alterations in the GM were analyzed by full-length 16S ribosomal RNA (rRNA) gene sequencing. The frequencies of AG genotype and A allele of VDR rs1544410 in aMCI group were significantly higher than that in NC group (genotype: p = 0.002, allele: p = 0.003). Patients with aMCI showed an abnormal GM composition compared with NC group. Interestingly, significant differences in GM composition were found between aMCI and NC group among individuals with AG genotype, as well as between individuals with AG and GG genotype of VDR rs1544410 among patients with aMCI. These results implicated that the crosstalk between gut microflora and vitamin D receptor variants are associated with the risk of aMCI in Chinese elderly population.

Genetic Variability of the Vitamin D Receptor Affects Susceptibility to Parkinson's Disease and Dopaminergic Treatment Adverse Events.

Vitamin D is a lipid-soluble molecule and an important transcriptional regulator in many tissues and organs, including the brain. Its role has been demonstrated also in Parkinson’s disease (PD) pathogenesis. Vitamin D receptor (VDR) is responsible for the initiation of vitamin D signaling cascade. The aim of this study was to assess the associations of VDR genetic variability with PD risk and different PD-related phenotypes. We genotyped 231 well characterized PD patients and 161 healthy blood donors for six VDR single nucleotide polymorphisms, namely rs739837, rs4516035, rs11568820, rs731236, rs2228570, and rs1544410. We observed that VDR rs2228570 is associated with PD risk (p < 0.001). Additionally, we observed associations of specific VDR genotypes with adverse events of dopaminergic treatment. VDR rs1544410 (GG vs. GA + AA: p = 0.005; GG vs. GA: p = 0.009) was associated with the occurrence of visual hallucinations and VDR rs739837 (TT vs. GG: p = 0.036), rs731236 (TT vs. TC + CC: p = 0.011; TT vs. TC: p = 0.028; TT vs. CC: p = 0.035), and rs1544410 (GG vs. GA: p = 0.014) with the occurrence of orthostatic hypotension. We believe that the reported study may support personalized approach to PD treatment, especially in terms of monitoring vitamin D level and vitamin D supplementation in patients with high risk VDR genotypes.

Association of genetic polymorphism in Vitamin D receptor and Paraoxonase I genes with type II diabetes mellitus patients in rural South Western Maharashtra

Background: Type II diabetes mellitus (T2DM) is increasing at an alarming rate in urban as well as rural parts of India. Change in life-style, dietary habits, aging, environmental factors contribute to developing this disorder, T2DM is a polygenic disorder which involves large number of genes interacting with each other and the environment to manifest itself phenotypically. Aims and Objectives: In the present study, we investigated the association of Vitamin D receptor (VDR) and Paraoxonase I (PON I) gene polymorphisms with T2DM patients among rural population in South western Maharashtra. Materials and Methods: The study groups included healthy non-diabetic control group (n = 120), non-obese diabetic group (n = 120), obese diabetic group (n = 120) from the same geographical region. The single nucleotide polymorphisms (SNPs) amongst these groups were studied using Polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) for VDR and PON I genes. Results and Conclusion: Amongst the studied genes VDR SNP rs1544410 [OR 0.24 (0.1-0.63); P 0.005] and Paraoxonase I SNP rs854560 (OR 0.47 (0.26-0.84); P 0.015) had a protective effect against T2DM for non-obese individuals. Whereas only VDR SNP rs1544410 [OR 0.025 (0.003-0.91); P 0.001] had a protective effect in case of obese individuals. The findings suggest greater gene-gene interaction and gene-environment interactions influence the phenotypic outcomes of genetic polymorphisms.

Association analysis of pulmonary tuberculosis and vitamin D Receptor Gene Polymorphisms of Han population in Western China

ObjectiveTo investigate the associations between single nucleotide polymorphism (SNP) of vitamin D receptor (VDR) gene and tuberculosis (TB) infection risk. Methods597 newly diagnosed pulmonary tuberculosis (PTB) patients from the Han population in Western China were randomly selected while 901 healthy subjects were divided into control group from September 2015 to September 2018. In the case-control study, 21 SNPs within the VDR gene were genotyped. Use SPSS 19.0 statistical software, SNP statistical software (Plink) and Pub-med network database to analyze the correlation between VDR SNP and PTB susceptibility. ResultsThe 14 SNPs of VDR gene screened in the experiment were consistent with the frequency of PTB-related and minor alleles> 5% in HapMap Asian population. Three SNPs (rs58379944, rs11574012, rs12581281) were correlated with PTB by x2 analysis. The rs58379944, rs11574012 alleles “G" and rs12581281 alleles “A" in genotype analysis were susceptible to tuberculosis. In the genotype analysis, allele “G" of rs58379944 and rs11574012 and allele “A" of rs12581281 provided protection against PTB infection. Conclusionrs58379944, rs12581281 and rs11574012 allelic variants in VDR gene were found to be closely associated with PTB infection in the Han population in Western China. The protection it achieved may be one of the reasons for reducing the infection rate.

Association of Vitamin D receptor gene polymorphisms and clinical/severe outcomes of COVID-19 patients.

IntroductionGrowing evidence documented the critical impacts of vitamin D (VD) in the prognosis of COVID-19 patients. The functions of VD are dependent on the vitamin D receptor (VDR) in the VD/VDR signaling pathway. Therefore, we aimed to assess the association of VDR gene polymorphisms with COVID-19 outcomes.MethodsIn the present study, eight VDR single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 500 COVID-19 patients in Iran, including 160 asymptomatic, 250 mild/moderate, and 90 severe/critical cases. The association of these polymorphisms with severity, clinical outcomes, and comorbidities were evaluated through the calculation of the Odds ratio (OR).ResultsInterestingly, significant associations were disclosed for some of the SNP-related alleles and/or genotypes in one or more genetic models with different clinical data in COVID-19 patients. Significant association of VDR-SNPs with signs, symptoms, and comorbidities was as follows: ApaI with shortness of breath (P ˂ 0.001) and asthma (P = 0.034) in severe/critical patients (group III); BsmI with chronic renal disease (P = 0.010) in mild/moderate patients (group II); Tru9I with vomiting (P = 0.031), shortness of breath (P = 0.04), and hypertension (P = 0.030); FokI with fever and hypertension (P = 0.027) in severe/critical patients (group III); CDX2 with shortness of breath (P = 0.022), hypertension (P = 0.036), and diabetes (P = 0.042) in severe/critical patients (group III); EcoRV with diabetes (P ˂ 0.001 and P = 0.045 in mild/moderate patients (group II) and severe/critical patients (group III), respectively). However, the association of VDR TaqI and BglI polymorphisms with clinical symptoms and comorbidities in COVID-19 patients was not significant.ConclusionVDR gene polymorphisms might play critical roles in the vulnerability to infection and severity of COVID-19, probably by altering the risk of comorbidities. However, these results require further validation in larger studies with different ethnicities and geographical regions.

Evaluation of vitamin D receptor gene polymorphisms in patients with differentiated thyroid carcinomas and nodular goiter.

The role of vitamin D has previously been determined in autoimmune and malignant thyroid diseases. We aimed to identify the haplotype distribution of single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene, which has been suggested to play a role in the pathogenesis of differentiated thyroid cancers and benign thyroid diseases. Two hundred and sixteen patients, 113 with benign and 103 with differentiated thyroid cancers, together with the same number of healthy controls, were included in the study. FokI, BsmI, ApaI, and TaqI SNPs in VDR were analyzed in all participants using the PCR-RFLP method. When the patients with differentiated thyroid cancers or the patients with nodular goiter and control cases were compared for BsmI, ApaI or TaqI polymorphisms, three genotype distributions (BB, Bb, bb; AA, Aa, aa; TT, Tt, tt) were found to not differ significantly. When the patients with differentiated thyroid cancers and control cases were compared for the FokI polymorphism in the VDR gene, the three genotype distributions (FF, Ff, ff) did not differ. However, in patients with nodular goiter, the FF genotype in the FokI polymorphism of the VDR gene was found to be statistically significantly higher (P=0.033). This is the first study in the literature evaluating the role of VDR gene SNPs in nodular goiter. We can suggest that SNP distribution in the VDR gene is not associated with malignancy but may cause some alterations in thyrocyte morphology and functions.

The role of single nucleotide polymorphisms of IL-1A -889C>T (rs1800587), TNF-A -238G>A (rs361525), and VDR TaqI (rs731236) on susceptibility to herniated nucleus pulposus: a systematic review and meta-analysis.

Background: The pathogenesis of herniated nucleus pulposus (HNP) is complex and may involve the wide variety of gene polymorphism. However, the reports from the existing studies are inconclusive. The objective of this study was to determine the role of single nucleotide polymorphisms (SNPs) in interleukin 1 alpha ( IL-1A), tumor necrosis factor-alpha ( TNF-A), and vitamin D receptor ( VDR) genes on the susceptibility to herniated nucleus pulposus (HNP). Methods: Four databases (PubMed, Embase, Cochrane, and Web of Science) were searched as of April 1 st, 2021. Authors, publication year, targeted genes, genotype and allele frequency in each case and control groups were collected. Newcastle-Ottawa scale was used to evaluate the publication quality. The pooled estimates of association of IL-1A -889C>T (rs1800587), TNF-A -238G>A (rs361525), and VDR TaqI (rs731236) and susceptibility to HNP were assessed using Z test. Results: We screened 3,067 unique studies for eligibility and three, two and nine case-controlstudies on IL-1A -889C>T, TNF-A -238G>A, and VDR TaqI were included, respectively, in our meta-analysis. The studies consisting 369 HNP cases and 433 controls for IL-1A -889C>T, 252 cases and 259 controls for TNF-A -238G>A and 1130 cases and 2096 controls for VDR TaqI. Our pooled estimates indicated that there was no significant association of those SNPs with the susceptibility to HNP in any genotype, dominant model, recessive model, or allele comparations. Conclusion: Although individual studies suggested the important role of gene expression dysregulation associated with SNPs in IL-1A, TNF-A, and VDR, our data indicated that IL-1A -889C>T, TNF-A -238G>A, and VDR TaqI had weak association with HNP susceptibility in both genotypes and allele distributions. However, since heterogeneity was identified among studies included in this meta-analysis, further meta-analysis with a larger population and subgroup analysis on specific population are warranted to support this finding.

Vitamin D Receptor Gene Polymorphisms and Risk of Knee Osteoarthritis: Possible Correlations with TNF-α, Macrophage Migration Inhibitory Factor, and 25-Hydroxycholecalciferol Status.

Osteoarthritis (OA) etiology and pathogenesis not yet fully understood. We studied the role of vitamin D receptor single-nucleotide polymorphisms (VDR-SNPs), vitamin D3, serum and synovial macrophage migration inhibitory factor (MIF), and tumor necrosis factor-α (TNF-α) in the development and progression of knee OA (KOA). This study included 205 Egyptian subjects (105 patients with KOA and 100 unrelated, healthy matched subjects selected as controls). The patient group was divided into three groups according to KOA severity (mild, moderate, and severe), with 35 patients in each group. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used for the ApaI and TaqI SNPs. Vitamin D, serum and synovial TNF-α, and MIF assays were performed using ELISA kits. There were significantly lower serum levels of 25-hydroxycholecalciferol with significant increasing TNF-α and MIF levels in relation to disease severity among the cases (all: p˂0.05).Wild homozygous and heterozygous mutant genotypes (GG+GT) and G allele of ApaI demonstrated risk for KOA development, with odds ratio OR = 6.313 (95% confidence interval (CI) 2.074-19.210) and OR = 1.532 (95%CI 1.013-2.317), respectively. Homozygous mutant CC genotype and C allele of TaqI could be considered a risk factor associated with KOA development, with OR = 2.667 (95%CI 1.270-5.601) and OR = 0.737 (95%CI 0.496-1.095), respectively. VDR-SNPs, vitamin D3, TNF-α, and MIF could play an essential role in the pathogenesis and progression of KOA with mechanistic associations.

The role of 25-hydroxyvitamin-D3 and vitamin D receptor gene in human periodontal ligament fibroblasts as response to orthodontic compressive strain: an in vitro study

BackgroundThis study aimed to investigate, if different physiological concentrations of vitamin D (25(OH)D3) and single nucleotide polymorphisms in vitamin D receptor (VDR) gene have an impact on gene expression in human periodontal ligament (hPDL) fibroblasts induced by simulated orthodontic compressive strain.MethodsA pool of hPDL fibroblasts was treated in absence or presence of 25(OH)D3 in 3 different concentrations (10, 40 and 60 ng/ml). In order to evaluate the role of single nucleotide polymorphisms in the VDR gene, hPDL fibroblasts from 9 patients were used and treated in absence or presence of 40 ng/ml 25(OH)D3. Each experiment was performed with and without simulated orthodontic compressive strain. Real-time PCR was used for gene expression and allelic discrimination analysis. Relative expression of dehydrocholesterol reductase (DHCR7), Sec23 homolog A, amidohydrolase domain containing 1 (AMDHD1), vitamin D 25-hydroxylase (CYP2R1), Hydroxyvitamin D-1-α hydroxylase, receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), cyclooxygenase-2 (COX-2) and interleukin-6 (IL6) was assessed. Three single nucleotide polymorphisms in VDR were genotyped. Parametric or non-parametric tests were used with an alpha of 5%.ResultsRANKL, RANKL:OPG ratio, COX-2, IL-6, DHCR7, CYP2R1 and AMDHD1 were differentially expressed during simulated orthodontic compressive strain (p < 0.05). The RANKL:OPG ratio was downregulated by all concentrations (10 ng/ml, 40 ng/ml and 60 ng/ml) of 25(OH)D3 (mean = 0.96 ± 0.68, mean = 1.61 ± 0.66 and mean = 1.86 ± 0.78, respectively) in comparison to the control (mean 2.58 ± 1.16) (p < 0.05). CYP2R1 gene expression was statistically modulated by the different 25(OH)D3 concentrations applied (p = 0.008). Samples from individuals carrying the GG genotype in rs739837 presented lower VDR mRNA expression and samples from individuals carrying the CC genotype in rs7975232 presented higher VDR mRNA expression (p < 0.05).ConclusionsSimulated orthodontic compressive strain and physiological concentrations of 25(OH)D3 seem to regulate the expression of orthodontic tooth movement and vitamin-D-related genes in periodontal ligament fibroblasts in the context of orthodontic compressive strain. Our study also suggests that single nucleotide polymorphisms in the VDR gene regulate VDR expression in periodontal ligament fibroblasts in the context of orthodontic compressive strain.

The role of single nucleotide polymorphisms of IL-1A -889C&gt;T (rs1800587), TNF-A -238G&gt;A (rs361525), and VDR TaqI (rs731236) on susceptibility to herniated nucleus pulposus

Background: The pathogenesis of herniated nucleus pulposus (HNP) is complex and may involve the wide variety of gene polymorphism. However, the reports from the existing studies are inconclusive. The objective of this study was to determine the role of single nucleotide polymorphisms (SNPs) in interleukin 1 alpha (IL-1A), tumor necrosis factor-alpha (TNF-A), and vitamin D receptor (VDR) genes on the susceptibility to herniated nucleus pulposus (HNP). Methods: Four databases (PubMed, Embase, Cochrane, and Web of Science) were searched as of April 1 st, 2021. Authors, publication year, targeted genes, genotype and allele frequency in each case and control groups were collected. Newcastle-Ottawa scale was used to evaluate the publication quality. The pooled estimates of association of IL-1A -889C&gt;T (rs1800587), TNF-A -238G&gt;A (rs361525), and VDR TaqI (rs731236) and susceptibility to HNP were assessed using Z test. Results: We screened 3,067 unique studies for eligibility and three, two and nine case-control studies on IL-1A -889C&gt;T, TNF-A -238G&gt;A, and VDR TaqI were included, respectively, in our meta-analysis. The studies consisting 369 HNP cases and 433 controls for IL-1A -889C&gt;T, 252 cases and 259 controls for TNF-A -238G&gt;A and 1130 cases and 2096 controls for VDR TaqI. Our pooled estimates indicated that there was no significant association of those SNPs with the susceptibility to HNP in any genotype, dominant model, recessive model, or allele comparations. Conclusion: Although individual studies suggested the important role of gene expression dysregulation associated with SNPs in IL-1A, TNF-A, and VDR, our data indicated that IL-1A -889C&gt;T, TNF-A -238G&gt;A, and VDR TaqI had weak association with HNP susceptibility in both genotypes and allele distributions. However, since heterogeneity was identified among studies included in this meta-analysis, further meta-analysis with a larger population and subgroup analysis on specific population are warranted to support this finding.