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PubMed2026

Association of Vitamin D Receptor Gene Polymorphism (FokI) with Susceptibility to Musculoskeletal Tuberculosis: A Case-Control Study from Central India.

AIM AND BACKGROUND: Musculoskeletal tuberculosis (MSKTB) constitutes a significant proportion of extra-pulmonary tuberculosis (TB), particularly in developing countries like India. While host genetic factors are known to influence susceptibility to TB, the Vitamin D receptor (VDR) gene, particularly the FokI polymorphism, has been implicated in immune regulation and susceptibility to pulmonary and extra-pulmonary TB, data on genetic predisposition to MSKTB remain limited. The present study aimed to investigate the role of the VDR FokI gene polymorphism in determining susceptibility to MSKTB. MATERIALS AND METHODS: This study included 110 patients with confirmed MSKTB and 112 controls without TB, recruited from a tertiary care institution over a 3-year period. Clinical and demographic data were obtained. Genomic DNA was extracted from peripheral venous blood samples, and VDR FokI polymorphism was detected using polymerase chain reaction-based restriction fragment length polymorphism analysis. Genotype and allele frequencies were compared using a Chi-square test, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS: The ff genotype was significantly more frequent in cases (17.3%) compared to controls (9.8%) and was associated with increased risk of MSKTB (OR = 2.30, 95% CI: 1.03-5.15, P = 0.04). The polymorphic f allele frequency was also significantly higher in cases than controls (38.2% vs. 28.1%; OR = 1.58, 95% CI: 1.05-2.37, P = 0.023). However, the dominant and recessive genetic models showed a non-significant association. Demographically, MSKTB was more common among females, individuals from rural backgrounds, those of lower socioeconomic status, and those with low body mass index. CONCLUSION: The VDR FokI polymorphism, particularly the ff genotype and f allele, is associated with increased susceptibility to MSKTB. These findings highlight the potential role of genetic factors in MSKTB and may aid in identifying at-risk populations.

FokI polymorphism↗

PubMed2026

Evaluating Associations Between Ankylosing Spondylitis, Torque Teno Virus and Polymorphisms in Interleukin 6 and Vitamin D Receptor Genes.

The etiology of ankylosing spondylitis (AS) is complex and not yet fully understood. Interleukin-6 (IL-6), vitamin D and the vitamin D receptor (VDR) play an important role in modulating immune response, and Torque teno virus is considered a marker of immune status. This case-control study aimed to investigate the predisposition to AS. A total of 85 patients with AS and 100 clinically healthy individuals were included. VDR polymorphisms (rs2228570, rs1544410, rs7975232, rs731236) were genotyped using the PCR-RFLP technique, while for the IL-6 -174 G>C (rs1800795) polymorphism the tetra-primer ARMS-PCR technique was used. The presence of TTV was detected using the hemi-nested PCR technique. Our findings indicate a statistically significant association between TTV and AS (p = 0.035). C allele of both rs1800795 polymorphism in main groups (p = 0.027) and rs731236 polymorphism in women subgroups (p = 0.036) may be linked to an increased susceptibility to AS. However, none of these associations reach statistical significance after Bonferroni correction. Furthermore, within female subgroups, a significant association was found between the T allele of rs1544410 polymorphism and AS (p = 0.000038, corrected p = 0.00076). A significant association was also observed between the TT genotype of rs2228570 polymorphism, TTV and AS (p = 0.029). Haplotype analysis revealed that certain VDR haplotypes may confer either a protective effect against AS or an increased risk of developing the condition. Notably, rs1544410 polymorphism or a linked polymorphism may influence AS susceptibility. In conclusion, our data suggest that TTV and VDR polymorphisms may be associated with an increased risk of developing AS, indicating that these markers could potentially be used in the future for earlier diagnosis and more targeted treatment of the disease.

Torque teno virus↗

PubMed2024

The association between vitamin D receptor gene polymorphism FokI and type 2 diabetic kidney disease and its molecular mechanism: a case control study.

BACKGROUND: The role of the vitamin D receptor single nucleotide polymorphism FOKI (VDR-FOKI) (rs2228570) in genetic susceptibility to type 2 diabetic kidney disease (T2DKD) remains uncertain. This study investigated the relationship between VDR-FOKI and T2DKD within the Chinese Plateau Han population and analyzed the underlying mechanisms. METHODS: A total of 316 subjects were enrolled, including 44 healthy adults, 114 individuals with type 2 diabetes mellitus (T2DM), and 158 patients with T2DKD. According to the 2023 American Diabetes Association Diabetes Guidelines, patients with T2DKD were categorized into low-medium-risk and high-risk groups based on estimates of glomerular filtration rate and urinary albumin-to-creatinine ratio. The VDR-FokI genotypes of all participants were identified using the Taqman probe and classified as homozygous mutant genotypes (C/C or FF), heterozygous mutant genotypes (C/T or Ff), and homozygous wild genotypes (T/T or ff). Plasma levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase activity (SOD) were assessed in T2DKD patients with FF and ff genotypes. Additionally, the levels of plasma VDR, GPX4, and P53 were determined using ELISA, while the relative expressions of VDR mRNA, GPX4 mRNA, and TP53 mRNA in whole blood were measured by RT-qPCR. RESULTS: The T2DM patients with the ff genotype exhibited a 2.93-fold increased likelihood of developing T2DKD compared to those with the FF genotype (ORadjusted = 2.93; 95% CI: 1.142-7.513). Additionally, they were 2.01 times more likely to develop T2DKD than individuals with the FF and Ff genotypes (ORadjusted = 2.01; 95% CI: 1.008-4.006). However, no significant differences in VDR-FokI genotype distribution were observed between the healthy control group and the T2DM group, as well as between the low-medium-risk and high-risk groups of T2DKD. Furthermore, T2DKD patients with the ff genotype had significantly higher plasma levels of MDA compared to those with the FF genotype. In contrast, plasma GSH and SOD content was significantly lower in the ff genotype patients (P < 0.05). Additionally, the GPX4 concentration in ff genotype patients was significantly lower than in FF genotype patients [14.88 (11.32,22.39) vs. 12.76 (8.55,13.75), P = 0.037]. Nevertheless, no statistically significant difference was observed in the expression of VDRmRNA, GPX4mRNA, TP53mRNA, plasma VDR, and plasma P53. CONCLUSIONS: The ff genotype of VDR-FokI is a risk factor for T2DKD, and the potential mechanism may be related to ferroptosis. However, It is not associated with T2DM or the progression of T2DKD.

Humans↗

PubMed2024

In vivo vitamin D target genes interconnect key signaling pathways of innate immunity.

The vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), its nuclear receptor VDR (vitamin D receptor) and hundreds of their target genes are not only key regulators of calcium homeostasis, but also important modulators of the immune system. Innate immune cells like monocytes use VDR for efficient differentiation and are very responsive to vitamin D. So far, most information on the gene regulatory function of vitamin D and its physiological impact had been obtained from in vitro studies using supraphysiological doses of 1,25(OH)2D3. Therefore, medical experiments like the study VitDHiD (NCT03537027), where 25 healthy individuals were supplemented once with a vitamin D3 bolus (80,000 IU), provide important insight into the response to vitamin D under in vivo conditions. In this study, we inspected 452 in vivo vitamin D target genes from peripheral blood mononuclear cells (PBMCs) detected in VitDHiD and found 61 of them involved in eight major KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways of innate immunity. Under in vivo conditions in healthy individuals vitamin D either silences five pathways of innate immunity, stabilizes two and increases one, so that acute inflammation is suppressed and the release of cytokines is kept under control. A ranking of the 61 target genes by inducibility, basal expression and multiple involvements in the pathways highlighted the genes NFKBIA (NFκB inhibitor alpha), NFKBIZ, FOSL2 (FOS like 2, AP1 transcription factor subunit), JDP2 (Jun dimerization protein 2), PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1), CLEC7A (C-type lectin domain containing 7A), DUSP6 (dual specificity phosphatase 6), NCF2 (neutrophil cytosolic factor 2), PLCB1 (phospholipase C beta 1), PLCG2 and TNFAIP3 (TNF alpha induced protein 3). In conclusion, vitamin D's in vivo effect on innate immunity in healthy adults is mediated by the interconnection of the pathways of neutrophil extracellular trap formation, Toll-like receptor, chemokine and phagosome signaling, NOD-like receptor, C-type lectin receptor, apoptosis and interleukin 17 through a limited set of proteins encoded by key target genes.

Humans↗

PubMed2003

Regulation of the bone-specific osteocalcin gene by p300 requires Runx2/Cbfa1 and the vitamin D3 receptor but not p300 intrinsic histone acetyltransferase activity.

p300 is a multifunctional transcriptional coactivator that serves as an adapter for several transcription factors including nuclear steroid hormone receptors. p300 possesses an intrinsic histone acetyltransferase (HAT) activity that may be critical for promoting steroid-dependent transcriptional activation. In osteoblastic cells, transcription of the bone-specific osteocalcin (OC) gene is principally regulated by the Runx2/Cbfa1 transcription factor and is stimulated in response to vitamin D(3) via the vitamin D(3) receptor complex. Therefore, we addressed p300 control of basal and vitamin D(3)-enhanced activity of the OC promoter. We find that transient overexpression of p300 results in a significant dose-dependent increase of both basal and vitamin D(3)-stimulated OC gene activity. This stimulatory effect requires intact Runx2/Cbfa1 binding sites and the vitamin D-responsive element. In addition, by coimmunoprecipitation, we show that the endogenous Runx2/Cbfa1 and p300 proteins are components of the same complexes within osteoblastic cells under physiological concentrations. We also demonstrate by chromatin immunoprecipitation assays that p300, Runx2/Cbfa1, and 1alpha,25-dihydroxyvitamin D(3) receptor interact with the OC promoter in intact osteoblastic cells expressing this gene. The effect of p300 on the OC promoter is independent of its intrinsic HAT activity, as a HAT-deficient p300 mutant protein up-regulates expression and cooperates with P/CAF to the same extent as the wild-type p300. On the basis of these results, we propose that p300 interacts with key transcriptional regulators of the OC gene and bridges distal and proximal OC promoter sequences to facilitate responsiveness to vitamin D(3).

Acetyltransferases↗

PubMed2026

Generation of spCAS9 expressing human mesenchymal stem cell line to study gene function during osteoblast differentiation.

Human bone marrow-derived stromal cells (hMSCs) are a great resource for studying how genes influence cell fate and differentiation into various cell types like osteoblasts, adipocytes, and chondrocytes, among other cell types. However, genetic manipulation of primary hMSCs has been challenging due to their short lifespan and cellular senescence after limited passaging. Their low and unstable transfection efficiency also complicates gene delivery or inactivation, hindering long-term functional studies. The limited lifespan has been effectively solved by immortalizing hMSCs with telomerase reverse transcriptase (hMSCs-TERT). The use of these cells is ideal for functional studies of osteoblast and adipocyte differentiation through genetic manipulation, providing a stable and reliable model. Here, we have engineered a stable CAS9 expressing hMSC-TERT cell line (hMSC-TERTCAS9) via lentiviral transduction. The constitutive expression of spCas9 enables efficient and reproducible gene editing. We demonstrate the potential of these hMSC-TERTCAS9 cells for generating gene disruptions using plasmid delivery of guide RNAs as a fast and efficient strategy for targeted genome editing. The edited cells can be sorted and expanded as single cells to obtain homogenous clonal cell lines with mono- as well as bi-allelic gene deletions, a crucial step for producing reliable experimental results. We further validate this cell line as a powerful tool for studying gene function during hMSC proliferation and differentiation, providing 3 distinct examples of its utility. Through the generation of indels, single-cell sorting, and clonal selection, we have efficiently inactivated the vitamin D receptor and created both larger (256 nucleotides) gene disruptions in Forkhead box protein O1 and precise removals of a small genomic sequence (73 nucleotides) coding for microRNA MIR675. This novel hMSC-TERTCAS9 cell line represents a significant advancement, offering a stable, efficient, and versatile platform for advanced genetic studies, high-throughput screening, and the creation of reliable cellular disease models.

CRISPR-Cas9↗

PubMed2025

Transcriptomic profile induced by calcitriol in CaSki human cervical cancer cell line.

The vitamin D endocrine system, primarily mediated by its main metabolite calcitriol and the vitamin D receptor (VDR), plays a critical role in numerous human physiological processes, ranging from calcium metabolism to the prevention of various tumors, including cervical cancer. In this study, we comprehensively investigated the genomic regulatory effects of calcitriol in a cervical cancer model. We examined the transcriptional changes induced by calcitriol in CaSki cells, a cervical cell line harboring multiple copies of HPV16, the primary causal agent of cervical cancer. Our microarray findings, revealed that calcitriol regulated over 1000 protein-coding genes, exhibiting a predominantly repressive effect on the CaSki cell transcriptome by suppressing twice as many genes as it induced. Calcitriol decreased EPHA2 and RARA expression while inducing KLK6 and CYP4F3 expression in CaSki cells, as validated by qPCR and Western blot. Functional analysis demonstrated that calcitriol effectively inhibited key processes involved in cancer progression, including cell proliferation and migration. This was further supported by the significant downregulation of MMP7 and MMP13 mRNA levels. Our microarray results also showed that, in addition to its effects on protein-coding genes, calcitriol significantly regulates non-coding RNAs, altering the expression of approximately 400 non-coding RNAs, including 111 microRNA precursors and 29 mature microRNAs, of which 17 were upregulated and 12 downregulated. Notably, among these calcitriol-regulated microRNAs are some involved in cervical cancer biology, such as miR-6129, miR-382, miR-655, miR-211, miR-590, miR-130a, miR-301a, and miR-1252. Collectively, these findings suggest that calcitriol exhibits a significant antitumor effect in this advanced cervical cancer model by blocking critical processes for tumor progression, underscoring the importance of maintaining adequate vitamin D nutritional status.

Humans↗

PubMed2026

Genome-wide chromatin profiling reveals a nonlimiting role for RXR in macrophage-like cells stimulated with multiple nuclear receptor agonists.

Retinoid X receptor (RXR) is an obligate heterodimerization partner for many nuclear receptors. In the absence of ligands, RXR occupies thousands of genomic regions, with its binding landscape predominantly determined by cell identity. In the presence of agonists of RXR or its partners, RXR occupancy is changed at a subset of binding regions. The characteristics of these ligand-responsive binding regions remain largely unexplored. We used ChIP-seq to profile RXR occupancy in PMA-differentiated THP-1 cells treated with agonists of RXR or partner receptors, including RARα, VDR, PPARδ, PPARγ, LXRs, and TR, or a "cocktail" containing multiple agonists. The RXR agonist LG268 produced a stronger increase in RXR occupancy than any of the six partner-receptor agonists or their combination. The relevance of ligand-induced RXR peaks was confirmed by the analyses of motif enrichment and RXR occupancy at regulatory elements of target genes. RXR binding was investigated in more detail in cells treated with the VDR agonist, calcitriol. Calcitriol markedly enhanced VDR binding, but the corresponding increase in RXR occupancy was less pronounced. We found that both ligand-induced and unresponsive RXR peaks were involved in gene regulation, and only a small subset (∼3%) of calcitriol-regulated genes exhibited decreases in both RXR binding and mRNA levels in response to combined agonist treatment. These results support a model in which RXR functions as a nonlimiting module in a macrophage-like cell type, and interference between pathways is minimally attributable to RXR sequestration.

Humans↗

PubMed2025

Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants.

BACKGROUND AND AIMS: Deviations from the population mean in sleep duration have been associated with increased risk for developing dyslipidemia and atherosclerotic cardiovascular disease, but the mechanism of effect is poorly characterized. We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. METHODS: We collected data from 55 cohorts with a combined sample size of 732,564 participants (87 % European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20 % of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for one-degree of freedom tests of interaction and two-degree of freedom joint tests of the SNP-main and -interaction effect on lipid levels. RESULTS: The one-degree of freedom variant-sleep interaction test identified 10 novel loci (Pint<5.0e-9), and we additionally identify 7 loci within the two-degree of freedom analyses (Pjoint<5.0e-9 in combination with Pint<6.6e-6). Multiple loci, including those mapped to APSH (target for aspartic and succinic acid) and SLC8A1 showed biological plausibility and druggability potential based on literature. CONCLUSIONS: Collectively, the 17 (9 with short and 8 with long sleep) loci provided evidence into the biomolecular mechanisms underlying sleep-associated lipid changes, including potential involvement of the vitamin D receptor pathway. Collectively, these findings may contribute developing novel interventions for treating dyslipidemia in people with sleep disturbances.

Humans↗