Investigating the level of vitamin D receptor gene expression in two tumoral and healthy breast tissues in breast cancer patients and its association with prognostic factors.

BACKGROUND: Breast cancer is one of the most common cancers known among women. This study aimed to investigate the level of vitamin D receptor gene expression in two tumoral and healthy breast tissues in breast cancer patients and its association with prognostic factors. METHODS: This descriptive cross-sectional study was conducted in 2022 on 50 patients with high suspicion of breast cancer who were candidates for mastectomy and lumpectomy in a learning hospital. From the patients, two tissue samples were prepared, and there was a total of 100 samples. The samples were subjected to H/E staining and evaluated by a pathologist. The presence or absence of malignancy in each sample was confirmed by two pathologists, and HER2/ER/PR indices were determined. Descriptive and analytical statistical methods and SPSS version 22 software were used. RESULTS: The average age of the patients was 51.60 ± 11.22 years old, and the average tumor size was 3.17 ± 1.28. Most tumors were grade 2 (48%). The expression of HER2, ER, and PR was positive in 24, 64, and 54%, respectively. The largest number of cases were in stage 2A. The expression level of vitamin D receptor (VDR) gene in healthy tissue (2.08 ± 1.01) was higher than tumoral tissue (0.25 ± 1.38) (P = 0.001). In tumoral and healthy tissue, VDR expression was not significant according to tumor grade, HER2, ER, PR, LVI, LN, disease stage, age, and tumor size. CONCLUSIONS: The expression level of VDR in healthy tissue was significantly higher than tumoral tissue. However, there was no significant relationship between VDR and tumor grade, HER2, ER, PR, LVI, LN, disease stage, age, and tumor size.

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

OBJECTIVE: 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 AND METHODS: 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. RESULTS: 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. CONCLUSIONS: This study has demonstrated the possible effects of VDR rs731236 SNP on the locoregional recurrence and prognosis of supraglottic larynx cancer.

The role of interaction between vitamin D and VDR FokI gene polymorphism (rs2228570) in sleep quality of adults.

To evaluate association of vitamin D with sleep quality in adults and the influence of VDR-gene polymorphism FokI (rs2228570;A > G). Cross-sectional population-based study in adults, conducted in Brazil. The outcome was sleep-quality, evaluated by the Pittsburgh Sleep Quality Index. Vitamin D was determined by indirect electrochemiluminescence and classified as deficiency (VDD), 25(OH)D < 20 ng/mL in a healthy population or 25(OH)D < 30 ng/mL for groups at risk for VDD. FokI polymorphism in the VDR-gene was genotyped by qPCR and classified as homozygous wild (FF or AA), heterozygous (Ff or AG), or homozygous mutant (ff or GG). Multivariate logistic analysis was used to estimate the association between vitamin D and FokI polymorphism with sleep-quality. In a total of 1674 individuals evaluated, 53.6% had poor-sleep-quality, 31.5% had VDD, and the genotype frequency of the FokI polymorphism was 9.9% FF, 44.6% Ff, and 45.5% ff. In multivariate analysis, individuals with VDD had 1.51 times the chance of poor-sleep-quality, and individuals with the ff genotype had 1.49 times the chance of poor-sleep-quality (OR:1.49;95%CI:1.05-2.12) when compared to individuals with the FF or Ff genotype. In the combined analysis, individuals with VDD and ff genotype had more chance of poor-sleep-quality than individuals with sufficient vitamin D and genotype Ff or FF (OR:2.19;95%CI:1.27-3.76). Our data suggest that VDD and VDR FokI gene polymorphism are associated with poor-sleep-quality, and combining the two factors increases the chance of poor-sleep-quality compared to separate groups.

Delving the vitamin D receptor variation and expression profiles in the context of type 2 diabetes among families.

BACKGROUND: Vitamin D is essential for insulin secretion and sensitivity. Consequently, its inadequacy is linked to higher insulin resistance and Type 2 Diabetes (T2D). The Vitamin D receptor (VDR) gene is one potential candidate for T2D, and multiple polymorphisms in VDR have been examined in various populations, but no conclusive answers have been provided. OBJECTIVES: This study was designed to evaluate the susceptibility of VDR gene polymorphism and its expression in diabetic families in Pakistan. METHODOLOGY: In this family-based study, twenty diabetic families with a positive family history of T2D and at least three T2D patients were recruited from outpatient clinics and public hospitals. The current study comprised 143 individuals with 55 affected and 88 unaffected individuals. Blood samples of the selected families were collected. DNA was extracted from the collected samples and the PCR-RFLP method was followed to identify the genotyping and RT-qPCR for expression. Phenotypic and genotypic pedigrees of the families were developed by the progeny online tool. The association values of SNPs were determined by TDT and DFAM analysis implemented on Plink software. RESULTS: The results explained a significant familial aggregation among phenotypic characters including Age, Gender, BMI (body mass index), age of disease diagnosis, disease duration, and blood pressure in the probands, affected FDRs (First Degree Relatives) and affected SDRs (Second Degree Relatives). A significant association of rs731236 C/T (OR = 1.522), rs2228570 C/T (OR = 1.327) with p < 0.05. Whereas, for rs1544410 G/A (OR = 0.9706) and rs7975232 T/G (OR = 0.7368) no considerable association evidence was seen (p > 0.05) in families. The mRNA expression of VDR increased threefold (p = 0.0204) in patients compared to controls. Variation-based expression analysis exhibited that the rs2228570 genotype influences the expression. CONCLUSION: A linkage was found among the FDRs with probands. Variation in the gene VDR at loci rs731236 and rs2228570 was associated with familial T2D. However further research is required to explore more genetic factors that could influence T2D risks in families.

Vitamin D receptor gene polymorphism in Egyptian multiple sclerosis patients.

One of the most common neurological illnesses in the world is multiple sclerosis (MS), a chronic autoimmune demyelinating disease of the central nervous system (CNS). MS has both a genetic and an environmental origin. In terms of environmental factors, vitamin D deficiency is one of the most important risk factors and closely connected with gene polymorphisms involved in vitamin D metabolism, transport, or activity. Since vitamin D activity requires a receptor-mediated response, any changes to the vitamin D receptor (VDR) may have an effect on the pathophysiology of the disease. In this study, we aimed to identify the relationship between VDR gene polymorphisms, FokI A>G (rs2228570), ApaI A>C (rs7975232) and BsmI C>T (rs1544410) and MS. FokI, ApaI and BsmI genotypes were determined in 50 patients with relapsing remitting MS (RRMS) and in 50 control subjects. DNA was isolated from blood samples, and then FokI, ApaI and BsmI gene polymorphisms were identified using allelic discrimination real time polymerase chain reaction (PCR) assay. The distribution of FokI, ApaI and BsmI polymorphisms did not show any significant differences between MS patients and controls. Thus, we concluded that there is no association between the studied VDR gene polymorphisms and MS.

Gene expression profiling of vitamin D metabolism enzymes in leukemia and lymphoma patients: molecular aspect interplay of VDR, CYP2R1, and CYP24A1.

BACKGROUND: Vitamin D deficiency is prevalent among the Indonesian population, particularly in individuals diagnosed with leukemia-lymphoma. The regulation of vitamin D metabolism is influenced by the expression of several enzymes, such as CYP2R1, CYP24A1, and the vitamin D receptor (VDR). This study aimed to scrutinize the gene expression profiles in both mRNA and protein levels of VDR, CYP2R1, and CYP24A1 in leukemia and lymphoma patients. METHOD: The research was a cross-sectional study conducted at Cipto Mangunkusumo Hospital (RSCM) in Jakarta, Indonesia. The study included a total of 45 patients aged over 18 years old who have received a diagnosis of lymphoma or leukemia. Vitamin D status was measured by examining serum 25 (OH) D levels. The analysis of VDR, CYP2R1, and CYP24A1 mRNA expression utilized the qRT-PCR method, while protein levels were measured through the ELISA method. CONCLUSION: The study revealed a noteworthy difference in VDR protein levels between men and women. The highest mean CYP24A1 protein levels were observed in the age group > 60 years. This study found a significant, moderately positive correlation between VDR protein levels and CYP24A1 protein levels in the male and vitamin D sufficiency groups. In addition, a significant positive correlation was found between VDR mRNA levels and CYP2R1 mRNA levels, VDR mRNA levels and CYP2R1 mRNA levels, and CYP2R1 mRNA levels and CYP24A1 mRNA levels. However, the expression of these genes does not correlate with the protein levels of its mRNA translation products in blood circulation.

Vitamin D receptor gene BsmI (rs1544410) polymorphism: role in multiple sclerosis and genotype-phenotype correlations.

BACKGROUND: Multiple sclerosis (MS) has a complex pathophysiology which depends on many endogenous and exogenous factors. Vitamin D involvement has been largely studied in MS. The large distribution of the vitamin D receptor (VDR) in different immune cells is suggestive of an immunomodulatory role. The VDR gene polymorphisms have been proposed as potential risk factors for MS development or evolution with non-conclusive results. METHODS AND RESULTS: We conducted a cross-sectional study including patients ≥ 18 years, with a diagnosis of relapsing remitting MS according to the McDonald Criteria and having a minimum follow-up period of one year after starting a disease modifying therapy. Two study groups were compared based on the Multiple Sclerosis Severity Scale or MSSS: "a slow progressor" group for an MSSS ≤ 5, and a "fast progressor" group for an MSSS > 5. The rs1544410 VDR gene polymorphism was studied for all patients. Eighty patients were included. The fast progressor groups had a higher EDSS at onset, a higher total number of relapses, more frequent and shorter time to secondary progression. The progression profile was not statistically different between genotypes and alleles of the VDR gene polymorphism rs1544410. The CC genotype and wild-type allele exhibited a more aggressive disease phenotype with a higher number of relapses the first year, shorter time to secondary progression and cerebral atrophy on assessment. CONCLUSIONS: Our results suggest potential genotype-phenotype correlations for the rs1544410 VDR gene polymorphism in the disease course of MS. Future research on a larger scale is needed to confirm these findings.

The Distinct Regulation of the Vitamin D and Aryl Hydrocarbon Receptors in COVID-19.

(1) Background: SARS-CoV-2 affects several immune pathways, including the vitamin D (VDR) and the aryl hydrocarbon receptor pathways (AhR). The aim of the study was the evaluation of the VDR and AhR pathways in the blood of COVID-19 patients with regard to the severity of disease. (2) Methods: Observational, single-center, case-control design. A total of 240 samples were selected for exploration. Patients who tested negative for SARS-CoV-2 but suffered from other respiratory infections (ORIs) served as a control group. (3) Results: VDR-specific mRNA in the blood of patients with mild symptoms (131.2 ± 198.6) was significantly upregulated relative to the VDR expression of the ORI group (23.24 ± 42.60; p < 0.0001); however, VDR expression of critically ill patients showed an impaired upregulation (54.73 ± 68.34; p < 0.001). CYP27B1 expression was not significantly regulated during SARS-CoV-2 infection. There was a downregulation of VDR and CYP27B1 compared to survivors. There was no significant difference in 25(OH)-vitamin D3 levels between critically ill patients with regard to survival (24.3 ± 9.4 vs. 27.1 ± 11.3; p = 0.433). (4) Conclusion: The VDR and AhR pathways are distinctively regulated in patients suffering from COVID-19 depending on the severity of disease. A combination treatment of antiviral drugs and vitamin D substitution should be evaluated for potentially improved prognosis in COVID-19.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Influence of the BsmI polymorphism of the vitamin D receptor gene on the levels of vitamin D, inflammatory and oxidative stress profile in patients with cystic fibrosis supplemented with Colecalciferol megadose.

OBJECTIVE: Evaluate the influence of the BsmI polymorphism of the vitamin D receptor gene on vitamin D levels, and inflammatory and oxidative stress markers in patients with Cystic Fibrosis supplemented with cholecalciferol megadose. METHODS: We performed a single-arm, non-randomized pre- and post-study of 17 patients aged 5 to 20 years with cystic fibrosis diagnosed with vitamin D insufficiency/deficiency 25-hydroxy vitamin< 30 ng/mL. Individuals were genotyped for the BsmI polymorphism of the vitamin D receptor gene and all received cholecalciferol supplementation of 4,000 IU daily for children aged 5 to 10 years and 10,000 IU for children over 10 years of age for 8 weeks. Interviews were conducted with personal data, sun exposure, anthropometric and blood samples of 25-hydroxy vitamin parathormone, serum calcium, ultrasensitive C-reactive protein, alpha 1 acid glycoprotein, total antioxidant capacity, malondialdehyde and kidney and liver function. Inter- and intra-group assessment was assessed by paired t-test Anova test or its non-parametric counterparts. RESULTS: The individuals were mostly male and reported no adverse effects from the use of supplementation, 64 % had 25-hydroxy vitamin levels >30 ng/mL. Patients with BB and Bb genotypes showed increased serum levels of 25-hydroxy vitamin. The group with BB genotype showed a reduction in alpha 1 acid glycoprotein. And individuals with the bb genotype had high levels of malondialdehyde compared to the pre-intervention time. CONCLUSION: It is concluded that variations of the BsmI polymorphism of the vitamin D receptor gene have different responses in vitamin D levels and markers of inflammation and oxidative stress.

Association between vitamin D receptor gene polymorphisms and genetic susceptibility to benign prostatic hyperplasia: A systematic review and meta-analysis.

BACKGROUND: Benign prostatic hyperplasia (BPH) is one of the global public health challenges due to the complexity of its mechanisms of occurrence. Many studies have suggested that vitamin D receptor gene polymorphisms are associated with BPH susceptibility. Still, their conflicting findings need to be analyzed in aggregate to gain a better understanding. METHODS: We identified 10 trials involving 1539 BPH cases and 1915 controls through a systematic search of Embase using, data obtained from the Web of Science, PubMed, and China Knowledge Network databases as of December 31, 2021. A meta-analysis was performed to investigate the association between 4 constant polymorphisms of this associated vitamin D receptor gene (Fok-1, Bsm-1, Taq-1, and Apa-1) and BPH risk. RESULTS: In the overall population analysis, a significant positive association with BPH risk was found only in the Taq-1 variant (P < .001). Of these, the pure-hybrid model (95% confidence interval [CI] = 1.384-3.196), the heterozygous model (95% CI = 1.207-2.021), the dominant model (95% CI = 1.312-2.133) and the allelic inheritance model (95% CI = 1.205-1.730) showed low heterogeneity. In subtype analyses, Bsm-1 variants showed a significant association with BPH risk for both the recessive (95% CI = 0.100-0.943, P = .039) and over-dominant (95% CI = 1.553-3.100, P = 0) models in the Caucasian population, and for the recessive (95% CI = 1.242-3.283, P = .039) and over-dominant (95% CI = 0.281-0.680, P = 0) models in the Asian population. In addition, a high degree of heterogeneity was found in the subgroup analysis of the association between Fok-1 variants and BPH risk. CONCLUSION: Overall, there is an association between vitamin D receptor polymorphisms and BPH risk. Identification of BPH susceptibility by vitamin D receptor gene polymorphisms has potential.

Vitamin D deficiency and the vitamin D receptor (VDR) gene polymorphism rs2228570 (FokI) are associated with an increased susceptibility to hypertension among the Bangladeshi population.

Vitamin D receptor (VDR) gene is implicated in hypertension vulnerability due to its role in regulating the renin-angiotensin system (RAS) and blood pressure. In this case-control study, a carefully selected cohort of 111 hypertensive individuals and 100 healthy controls underwent serum analysis using HPLC to measure 25-hydroxy vitamin D levels. Polymorphic variations in the VDR gene were detected and characterized using the PCR-RFLP method. At first, lower 25-hydroxy vitamin D levels were observed in hypertensive individuals compared to controls (p<0.001). The genotype frequency of the VDR gene TaqI showed no significant difference between cases and controls (p>0.05). Similarly, no significant difference was found in the VDR gene BsmI genotype frequency between hypertensive patients and controls (p>0.05). However, a statistically significant distinction was observed in the VDR gene FokI genotype frequency between cases and controls (p<0.01). The odds ratios for FokI genotypes (CC, CT, TT, and CT+TT) were 1.0, 0.590, 1.566, and 0.963, respectively. Furthermore, serum 25-hydroxy vitamin D levels were significantly higher in control subjects compared to hypertensive patients across all genotypes of VDR (p<0.001). Hypertensive patients, excluding those with the FokI VDR gene CC genotype, exhibited significantly higher systolic blood pressure levels compared to the control group (p<0.05). Similarly, hypertensive subjects displayed elevated diastolic blood pressure levels compared to the control group (p<0.001). Overall, the results suggest the presence of a potential inverse correlation between serum 25-hydroxy vitamin D levels and hypertension. The association analysis conducted indicated that there is no significant association between TaqI and bsmI genotypic variants and the risk of developing hypertension. However, it was observed that VDR gene polymorphisms do have a clear association with hypertension susceptibility, as evidenced by the significantly higher occurrence of FokI genotypic variants in hypertensive patients. Our study therefore introduces the possibility of utilizing 25-hydroxy vitamin D deficiency and VDR gene polymorphisms as a biomarker for hypertension.

Interaction between Fokl polymorphism and vitamin D deficiency in the symptoms of mental disorders in adults: a population-based study.

Mental disorders are intricate and multifaceted and encompass social, economic, environmental, and biological factors. This study aimed to explore the potential association between vitamin D deficiency and anxiety and depression symptoms in adults, considering the role of the vitamin D receptor gene polymorphism FokI (rs2228570). This was a population-based cross-sectional study with stratified and cluster sampling, evaluating anxiety symptoms (AS) and depression symptoms (DS) in 1637 adults. Vitamin D levels were measured using electrochemiluminescence and were considered deficient when < 20 ng/mL in a healthy population or < 30 ng/mL in at-risk groups. Genotyping was performed using real-time polymerase chain reaction with TaqMan probes. The prevalence rates of AS, DS, and vitamin D deficiency were 23.5%, 15.8%, and 30.9%, respectively. No direct association was observed between vitamin D deficiency and AS or DS. However, interaction analysis revealed a combined effect of vitamin D deficiency and FokI for DS but not for AS. Individuals with vitamin deficiency and one or two copies of the altered allele of the FokI exhibited a higher prevalence of DS than individuals homozygous for the wild-type allele and vitamin D sufficiency. The interaction between vitamin D deficiency and the FokI polymorphism was associated with DS.

Association of the ESR1 (rs9340799), OLR1 (rs3736234), LIPC (rs2070895), VDR (rs2228570), and CETP (rs708272) Polymorphisms With Risk of Coronary Artery Disease in Iranian Patients.

BACKGROUND: Coronary artery disease (CAD) is a devastating illness and a leading cause of death worldwide, primarily caused by atherosclerosis resulting from a genetic-environmental interaction. This study aimed to investigate the relationship between the ESR1 (rs9340799), OLR1 (rs3736234), LIPC (rs2070895), VDR (rs2228570), and CETP (rs708272) polymorphisms, lipid profile parameters, and CAD risk in a southeast Iranian population. METHODS: A total of 400 subjects (200 CAD patients with hyperlipidemia and 200 healthy controls) were enrolled in this case-control study. Five selected polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: For all single nucleotide polymorphisms (SNPs), the population under study was in the Hardy-Weinberg equilibrium. The T-risk allele frequency of rs2228570 was associated with an increased risk of CAD. The TT and CT genotypes of rs2228570 had also been associated with the risk of CAD. Additionally, the TT genotype was associated with higher serum low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) levels. The GG genotype of the rs3736234 was associated with higher body mass index (BMI) and triglyceride (TG) levels, and the AA genotype of the rs708272 was associated with higher HDL-c levels. Based on these findings, we propose that the VDR (rs2228570) polymorphism was associated with serum HDL-c and LDL-c levels and may serve as potential risk factors for CAD within the Iranian population. Moreover, rs3736234 and rs708272 influence the concentrations of TG and HDL-c, respectively. CONCLUSION: These findings provided insights into the complex interplay between genetic variations, cardiovascular risk, and lipid metabolism.

MicroRNA-125b regulates vitamin D resistance by targeting CYP24A1 in the progression of gestational diabetes mellitus.

Vitamin D deficiency is prevalent in pregnancy and has been associated with increased occurrences of preeclampsia, cesarean delivery, neonatal bacterial vaginosis, and gestational diabetes. CYP24A1, recognized as a key factor in vitamin D metabolism homeostasis, encodes 24-hydroxylase responsible for converting 25(OH)D3 and 1,25(OH)2D3 into inactive metabolites. Recently, we have reported CYP24A1 overexpression in patients with gestational diabetes mellitus (GDM) and trophoblast cells exposed to hyperglycemia. In this study, we explored miRNA-mediated regulation of CYP24A1 in GDM progression, validating our findings through silencing experiments in a trophoblast cell line. In silico tools identified miR-125b-5p as a putative target of CYP24A1. Expression analysis revealed downregulation of miR-125b-5p in blood samples from early GDM and GDM compared to healthy pregnant women, positively correlating with vitamin D levels. Hyperglycemic exposure in human trophoblastic cell lines (BeWo) decreased miR-125b-5p expression, concomitant with an increase in CYP24A1. To confirm the regulatory role of miR-125b on CYP24A1, we transfected BeWo cells with antimiR-125b or miR-125b mimic. AntimiR-125b transfection heightened CYP24A1 levels, while miR-125b mimic overexpression resulted in decreased CYP24A1 expression. These findings establish miR-125b as a regulator of CYP24A1. To explore the influence of miR-125b on vitamin D metabolism, trophoblast cells overexpressing miR-125b were treated with 0.1 and 1 µM calcitriol. Hyperglycemic conditions exhibited a reduction in CYP24A1 levels. Collectively, our results indicate that miR-125b may regulate vitamin D metabolism by targeting CYP24A1, contributing to GDM progression. These findings may pave the way for understanding vitamin D resistance in concurrent GDM development and identifying novel miRNAs targeting CYP24A1.

The anti-aging effect of vitamin D and vitamin D receptor in Drosophila midgut.

Adult stem cells are pivotal for maintaining tissue homeostasis, and their functional decline is linked to aging and its associated diseases, influenced by the niche cells' environment. Age- and cancer-related reduction of vitamin D and its receptor levels are well documented in human clinical studies. However, the mechanisms through which the vitamin D/vitamin D receptor pathway contributes to anti-aging and extends life expectancy are not well understood. In this study, we aimed to determine the protective role of the vitamin D/vitamin D receptor pathway in differentiated enterocytes (ECs) during intestinal stem cell (ISC) aging. By utilizing a well- established Drosophila midgut model for stem cell aging biology, we revealed that vitamin D receptor knockdown in ECs induced ISC proliferation, EC death, ISC aging, and enteroendocrine cell differentiation. Additionally, age- and oxidative stress-induced increases in ISC proliferation and centrosome amplification were reduced by vitamin D treatment. Our findings suggest a direct evidence of the anti-aging role of the vitamin D/vitamin D receptor pathway and provides insights into the molecular mechanisms underlying healthy aging in Drosophila.

The Association of Vitamin D Receptor Gene Polymorphisms with Vitamin D, Total IgE, and Blood Eosinophils in Patients with Atopy.

BACKGROUND: In order to improve the control of atopic diseases, it is important to clarify the pathogenesis of atopy and identify its various triggers. Single nucleotide polymorphisms (SNPs) of the vitamin D receptor gene (VDR) may impact atopy. The aim of this study was to investigate the possible associations between VDR SNPs and vitamin D, total IgE, and eosinophils in atopy. METHODS: In total, 203 adults, including 122 patients with atopic diseases (45 with atopic dermatitis, 77 with allergic asthma) and 81 healthy controls, were involved in the study. The blood eosinophil count was determined with an automated hematology analyzer. Vitamin D and total immunoglobulin E (IgE) levels were evaluated using the ELISA method. Polymorphisms in the VDR gene were analyzed with real-time PCR using TaqMan probes. RESULTS: We analyzed six VDR single nucleotide polymorphisms and found a significant association between VDR rs731236 GG genotype and normal vitamin D levels in atopic patients and healthy subjects (OR 11.33; 95% CI: 1.049-122.388 and OR 4.04; 95% CI: 1.117-14.588, respectively, p < 0.05). Additionally, the study results revealed a significant relationship between the VDR rs2228570 GG genotype and normal vitamin D levels in patients with atopy and healthy subjects (OR 3.80; 95% CI: 1.190-12.134 and OR 2.09; 95% CI: 1.044-4.194, respectively, p < 0.05). The rs2228570 allele A was associated with decreased vitamin D levels in patients with atopy and healthy subjects (OR 0.28; 95% CI: 0.098-0.804 and OR 0.229; 95% CI: 0.069-0.761, respectively, p < 0.05). The VDR rs3847987 genotypes AA and AC were significantly associated with normal vitamin D levels in healthy subjects (OR 35.99; 95% CI: 6.401-202.446 and OR 4.72; 95% CI: 1.489-15.007, respectively, p < 0.05). In addition, a decreased amount of vitamin D was associated with atopic diseases such as atopic dermatitis and allergic asthma (OR 0.49; 95% CI: 0.439-1.308 and OR 0.58; 95% CI: 0.372-0.908, respectively, p < 0.05). The rs11168293 allele T was associated with the normal range of total IgE in atopy (OR 2.366; 95% CI: 1.133-5.027; p < 0.05). Significant associations were found between VDR rs731263 allele G, rs11168293 allele G, and increased blood eosinophil levels in patients with atopy (OR 0.319; 95% CI: 0.163-0.934 and OR 0.323; 95% CI: 0.112-0.935, respectively, p < 0.05). CONCLUSIONS: A decreased vitamin D level showed a significant relationship with atopic diseases (atopic dermatitis and allergic asthma). The association between the VDR gene polymorphisms rs2228570, rs731236, and rs11168293 and vitamin D, total IgE, and blood eosinophils in patients with atopy suggested that VDR polymorphisms and the vitamin D level should be considered when examining the factors associated with atopy.

Genetic Diversity in Bronchial Asthma Susceptibility: Exploring the Role of Vitamin D Receptor Gene Polymorphisms in Varied Geographic Contexts.

Bronchial asthma (BA) exhibits varying prevalence across global populations, prompting a comprehensive investigation into genetic and environmental determinants. Vitamin D is a potent immunomodulator capable of suppressing inflammatory signals in several cell types involved in the asthmatic response; it exerts effects on the immune system by binding to the nuclear vitamin D receptor (VDR). VDR gene genetic variations are affecting serum vitamin D levels with a possible role in the BA risk. The current study aimed to examine the complex interaction of various factors (genetic background, serum vitamin D levels, and geographic location) to identify differences in the influence of these factors on the susceptibility to asthma between populations at different latitudes. Focusing on Eastern European cohorts from Latvia and Lithuania and comparing them with published data on East Asian populations, we explore the impact of VDR gene polymorphisms on BA susceptibility. Genotyping four key VDR SNPs and assessing their association with 25-hydroxyvitamin D levels, our study unveils significant associations of the studied loci with the risk of asthma-both risk-reducing and increasing effects, differently distributed between Baltic and East Asian populations. The functional effects of in silico VDR gene genetic variations are also identified and discussed.

Vitamin D and Aging: Central Role of Immunocompetence.

The pro-hormone vitamin D3 is an important modulator of both innate and adaptive immunity since its biologically active metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) regulates via the transcription factor VDR (vitamin D receptor) the epigenome and transcriptome of human immune cells and controls in this way the expression of hundreds of vitamin D target genes. Since the myeloid linage of hematopoiesis is epigenetically programmed by VDR in concert with the pioneer factors PU.1 (purine-rich box 1) and CEBPα (CCAAT/enhancer binding protein α), monocytes, macrophages, and dendritic cells are the most vitamin D-sensitive immune cell types. The central role of the immune system in various aging-related diseases suggests that immunocompetence describes not only the ability of an individual to resist pathogens and parasites but also to contest non-communicative diseases and the process of aging itself. In this review, we argue that the individual-specific responsiveness to vitamin D relates to a person's immunocompetence via the epigenetic programming function of VDR and its ligand 1,25(OH)2D3 during hematopoiesis as well as in the periphery. This may provide a mechanism explaining how vitamin D protects against major common diseases and, in parallel, promotes healthy aging.

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.