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PubMed2026

Vitamin D Deficiency During Pregnancy Is Associated With Greater LDL-C Increase, Elevated β-Hydroxybutyrate and Altered Neonatal Metabolic Markers-A Secondary, Pooled Analysis of the Randomized, Controlled Vitamin D and Lifestyle for Gestational Diabetes Prevention Trial (DALI).

INTRODUCTION: Vitamin D (vitD) plays a role in metabolic regulation, including lipid metabolism and insulin sensitivity. During pregnancy, profound physiological changes in lipid handling and ketogenesis occur to support fetal development. However, the extent to which maternal vitamin D status influences these metabolic adaptations and fetal metabolic markers remains unclear. METHODS: In this secondary analysis, we examined lipid distribution throughout pregnancy-from before 20 weeks' gestation to delivery-in women with overweight or obesity, stratified by vitamin D status (deficiency, insufficiency, or sufficiency), assessing both maternal and cord blood. Main inclusion criteria were: age > =18 years, singleton pregnancy, < 20 weeks' gestation, BMI ≥ 29 kg/m2. Women with GDM < 20 weeks' gestation were excluded. In total, 962 pregnant women were divided into vitD deficient (< 30 nmol/L, n = 102), insufficient (30-50 nmol/L, n = 222) and sufficient (> 50 nmol/L, n = 638) groups. VitD levels and lipid concentrations were assessed at < 20, 24-28 and 35-37 weeks' gestation and in cord blood. RESULTS: Compared with vitD sufficient women, women with vitD deficiency had significantly larger increases in LDL-C throughout pregnancy and ß-OH-butyrate at 24-28 weeks' gestation, in adjusted analysis. VitD in cord blood was highest in offspring of mothers with vitD sufficiency. In cord blood, significantly higher ß-OH-butyrate was observed with vitD deficiency; lipid concentrations were similar between groups. CONCLUSIONS: Early vitamin D deficiency before 20 weeks of gestation was associated with altered metabolic trajectories during pregnancy, including greater increases in LDL cholesterol and ketone body concentrations in women with overweight or obesity, as well as higher cord blood ketone levels in their offspring. These findings suggest that early maternal vitamin D status may influence maternal and fetal metabolic adaptations, although causal relationships and clinical implications require further investigation. TRIAL REGISTRATION: Trial registered at ISRCTN registry (https://doi.org/10.1186/ISRCTN70595832) trial number ISRCTN70595832. Registration date 02/12/2011.

Humans↗

PubMed2025

Prevalence and determinants of profound vitamin D deficiency (25-hydroxyvitamin D <10 nmol/L) in the UK Biobank and potential implications for disease association studies.

BACKGROUND: 25-hydroxyvitamin D (25OHD) is the principal biomarker of vitamin D status. Values below the assay detection limit (<10 nmol/L) are often reported as missing. Thus the most severely deficient participants are excluded from research which can lead to inaccurate findings such as underestimated prevalence of deficiency, overlooked risk factors, and biased evaluation of disease associations. METHODS: In total 369,626 individuals from the UK Biobank cohort were included in this study. Data on 25OHD concentration and relevant demographic and lifestyle factors such as age, supplement intake, diet, and time spent outdoors were used in the analyses. Ambient UVB radiation was approximated for each participant. 25OHD was evaluated as a categorical outcome and we reintroduced participants with 25OHD values < 10 nmol/L (conventionally reported as missing values) back to the dataset. Adjusted regression models were used to investigate the determinants of profound (25OHD <10 nmol/L) and severe (10-25 nmol/L) vitamin D deficiency and to assess disease associations (with 25-50 nmol/L as the reference category). RESULTS: 1,784 (0.48 %) individuals were profoundly deficient and a further 47,226 (12.78 %) individuals were severely vitamin D deficient. The proportions of profoundly and severely deficient were highest among Asians, 9 % and 47 %, respectively. Ambient UVB radiation was the second strongest predictor: comparing the lowest vs. highest quartile, the risk of profound deficiency was 17-fold increased and that of severe deficiency 7.5-fold increased. Use of vitamin D supplements substantially reduced risk of profound (4.4-fold) and severe (2.5-fold) deficiency, as did fish intake (5- and 1.9-fold, respectively). Profound deficiency was more strongly associated with chronic illness, diabetes, and emphysema compared to severe deficiency. CONCLUSION: The prevalence of profound and severe vitamin D deficiency among Asian and Black ethnicities in the UK is high and requires targeted action. Solar radiation is potent in protecting against profound and severe vitamin D deficiency. Studies evaluating the relationship between vitamin D status and other health outcomes may be biased if profoundly deficient participants are excluded.

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↗

PubMed2024

Correlation between rs7041 and rs4588 polymorphisms in vitamin D binding protein gene and COVID-19-related severity and mortality.

BACKGROUND: The vitamin D binding protein (DBP) plays a critical role in both innate and adaptive immune systems, participating in several clinical conditions, including coronavirus disease 2019 infection severity, and mortality rate. The study aimed to investigate the correlation between rs7041 and rs4588 polymorphisms in the DBP gene and Coronavirus Disease-2019 (COVID-19) severity and mortality, in patients of Suez Canal University Hospitals in Ismailia, Egypt. METHODS: A case-control study enrolled 220 individuals; 140 COVID-19 patients and 80 healthy controls. Serum 25(OH) vitamin D levels were determined by the enzyme-linked immunosorbent assay (ELISA), and rs7041 and rs4588 polymorphisms of the DBP gene were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The study found that both groups had vitamin D deficiency, which was considerably lower in the COVID-19 patients group compared to controls. Among COVID-19 patients, there was a significant difference in vitamin D levels according to the disease severity indicating that vitamin D levels can be used as predictors of COVID-19 severity. Negative significant correlations between genetic variants rs4588 CA genotype and genetic variants rs7041 TT genotype and COVID-19 prevalence (p = 0.006 and 0.009 respectively) were proved. No significant correlations between all the genetic variants of both rs4588 and rs7041 and COVID-19 severity (p > 0.05). Positive significant correlations between both genetic variants rs4588 CA genotype and genetic variants rs7041 TG genotype and COVID-19 mortality (p = 0.029 and 0.031 respectively). CONCLUSION: vitamin D deficiency increased the severity of COVID-19. The DBP polymorphism correlated with vitamin COVID-19 prevalence and mortality.

Humans↗

PubMed2026

Vitamin D Supplementation Modulates Base Excision Repair (BER) Machinery in Systemic Sclerosis: A Prospective Longitudinal Study.

Systemic sclerosis (SSc) is a chronic, autoimmune, fibrotic disorder involving immune dysregulation, vascular abnormalities and progressive fibrosis. Although oxidative stress and defective DNA repair have been implicated in its pathogenesis, the impact of vitamin D on DNA repair pathways remains unclear. This study aimed to investigate the expression of DNA repair enzymes in SSc, explore their relationship with vitamin D status and assess the effects of vitamin D supplementation on the transcriptional expression of these enzymes. Peripheral blood samples were collected from 52 female patients with SSc and 31 age-matched healthy controls (HCs). Gene expression levels of base excision repair (BER) enzymes (APE1 and OGG1) and nucleotide excision repair (NER) enzymes (XPA and XPC) were analyzed. Serum vitamin D levels were measured and correlated with disease activity scores. In a prospective arm of the study, patients received six months of vitamin D supplementation and their DNA repair capacity was evaluated pre- and post-intervention. Baseline expression of APE1 and OGG1 was significantly lower in SSc patients than in HCs, whereas expression of the NER genes remained unchanged, indicating selective impairment of the BER pathway. Vitamin D deficiency was prevalent in SSc and inversely correlated with disease severity. Supplementation significantly increased serum vitamin D levels and up-regulated APE1 and OGG1 expression; while NER genes remained unaffected. These findings are consistent with evidence of elevated oxidative DNA lesions in SSc and support a mechanistic link between BER activity and the repair of oxidative DNA damage. SSc patients exhibit reduced transcription of BER-specific enzymes associated with vitamin D deficiency andrestoration of vitamin D levels partially rescues BER enzyme expression. These findingshighlight a potentially modifiable axis linking micronutrient status, genomic stability and disease activity and provide a rationale for investigating vitamin D optimization as an adjunctive strategy to enhance DNA repair and potentially attenuate inflammatory and fibrotic processes in SSc.

Humans↗

PubMed2026

Investigating the mechanisms linking vitamin D to coronary artery disease: A mediating proteomics Mendelian randomisation study.

Coronary artery disease (CAD) is a leading cause of mortality and morbidity globally, with its elevated rates of disability and death posing a significant public health concern. Vitamin D is a crucial bioactive compound involved in numerous physiological processes and has garnered considerable interest due to its potential health benefits. The association between vitamin D and CAD has been a prominent focus of scholarly investigation. However, there remains considerable debate regarding whether vitamin D confers protective effects against CAD, and the underlying mechanisms by which vitamin D influences CAD remain inadequately understood. Mendelian randomization analysis was performed using large-scale genome-wide association study data to examine the causal relationship between serum 25-hydroxyvitamin D (25(OH)D) levels and CAD. Plasma proteomics data were subsequently employed for mediation analysis, followed by enrichment analysis to identify intermediary metabolic or signaling pathways through which serum 25(OH)D may mediate the onset and progression of CAD. The Mendelian randomization analysis indicated that higher serum 25(OH)D levels were associated with a reduced risk of CAD (odds ratio [95% confidence interval]: 0.799 [0.643-0.993], P = .043). No evidence of pleiotropy (P = .949) or heterogeneity (P = .630) was observed in the results. The protein-mediated analysis identified 19 plasma proteins, including Serine/threonine-protein kinase TBK1, membrane associating domain domain-containing protein 2, and interleukin-17D, as key mediators through which reduced vitamin D levels contribute to the development of CAD. The mediation effects ranged from 4.85 to 34.49%. Following the identification of these 19 mediating proteins, 59 intermediary pathways were further pinpointed through which serum vitamin D influences CAD risk. Increased levels of 25(OH)D may reduce the risk of CAD. Further, plasma proteomics-mediated analyses have uncovered potential mechanisms through which 25(OH)D influences the development of CAD, offering a detailed framework for understanding the relationship between vitamin D deficiency and CAD progression. This provides novel evidence to support the recommendation of appropriate vitamin D supplementation as part of lifestyle guidance for CAD patients.

Coronary Artery Disease↗

PubMed2026

Vegan multinutrient supplementation significantly increases Omega-3 index and 25-OH-vitamin D status: a randomized, double-blind, placebo-controlled trial in healthy young vegans.

In this randomized, double-blind, placebo-controlled trial, 72 healthy vegan adults (aged 19-57 years) received a multinutrient supplement consisting of a vitamin and mineral supplement (providing 26 µg vitamin D) and an omega-3 supplement administered in either a single dose (EPA 98.7 mg, DHA 171.0 mg, additional vitamin D 36 µg, vitamin E 3.7 mg) or a double dose (EPA 197.4 mg, DHA 342.0 mg, additional vitamin D 72 µg, vitamin E 7.4 mg) or placebo capsules for 4 months. Nutrient biomarkers were assessed at baseline and at the end of the intervention after 4 months. An analysis of covariance was employed to test for between-group differences (p < 0.05) and adjusted for multiple testing using the Bonferroni-Holm method. Compared to the control group, which showed on average a significant decline in both the omega-3-index and 25-hydroxyvitamin D, participants in both intervention groups demonstrated significant increase in these parameters (p < 0.001). Although the double dose group exhibited numerically greater increases in omega-3 index and vitamin D compared to the simple dose group, the differences between these dosing regimens were not statistically significant. As expected, vitamin E levels remained unchanged, reflecting its inclusion solely for antioxidative protection in the omega-3 supplement rather than as a critical nutrient in vegan diets. In conclusion, supplementation significantly improved omega-3 and vitamin D status in healthy vegans, with no significant benefit from doubling the dose. Although clinical endpoints were not evaluated, improved nutrient status may have potential implications for health. The study has been registered at the German Clinical Trials Register (DRKS00028151).

Humans↗

PubMed2026

Effect of Peer Comparison Feedback and Professional Norms on Vitamin D Testing and Generic Medication Prescribing.

BACKGROUND: Organization for Economic Cooperation and Development (OECD) estimates suggest that 20% of health care spending is wasteful or even harmful. Previous interventions have had limited success in discouraging low-value care in medical practice. METHODS: We conducted a nationwide randomized controlled trial among primary care physicians (PCPs) in Switzerland (November 2020-December 2021). We randomly assigned PCPs to one of three intervention groups related to low-value care (vitamin D testing, generic prescribing, or a cost intervention) or a control group. This article reports results for the vitamin D testing and generic prescribing interventions compared with the common control group. PCPs in the intervention groups received a personalized information letter combining professional norms and peer comparison feedback about the low-value service (either vitamin D testing or prescribing of nongeneric medications). Primary endpoints were (1) the number of vitamin D tests per 100 patients and (2) the share of generic medications prescribed. We estimated average treatment effects using linear regression and assessed effect heterogeneity with a causal forest. RESULTS: A total of 618 PCPs were randomly assigned to the vitamin D intervention, 597 to the generic prescribing intervention and 601 to the common control group. The intervention reduced average vitamin D testing by 3.66 tests per 100 patients (95% confidence interval [CI], -5.42 to -1.89; P<0.001). The intervention did not increase average generic medication prescribing (mean difference, +0.57 percentage points; 95% CI, -0.68 to +1.81 percentage points; P=0.37). Heterogeneity analysis suggested that reductions in vitamin D testing among physician subgroups ranged from one to seven per 100 patients and that higher baseline generic prescribing rates were associated with increases in generic substitution following the intervention. No increases in low-value care were seen among those physicians with low baseline levels. CONCLUSIONS: Peer comparison letters emphasizing professional norms reduced vitamin D testing but did not increase generic medication prescribing. (Funded by the Swiss National Science Foundation; AEA Randomized Controlled Trials Registry no., AEARCTR-0004747.).

Humans↗

PubMed2025

Gestational vitamin D concentration and child cognitive development: a longitudinal cohort study in the Environmental influences on Child Health Outcomes Program.

BACKGROUND: Low vitamin D concentrations are common-especially among those with darker pigmented skin-and are frequently observed during pregnancy. Given its important role in brain development, inadequate gestational vitamin D may impair child cognitive development. OBJECTIVES: We aimed to evaluate associations of gestational vitamin D concentrations with childhood cognitive scores, explore whether this relationship differs by self-reported race, and examine sensitive exposure windows within pregnancy. METHODS: This prospective cohort study included 912 mother-child dyads (37.3% Black, 52.3% White) from the Environmental influences on Child Health Outcomes program. 25-hydroxyvitamin D [25(OH)D] concentrations were measured in prenatal or cord blood collected between 4 and 42 wk gestation (median: 23 wk). Children's cognition was assessed at ages 7-12 y using the NIH Toolbox Cognition Battery. Relationships of 25(OH)D and cognitive scores were examined using mixed-effects linear models adjusted for confounders. Potential sensitive periods were explored by estimating population 25(OH)D patterns across gestation for varying levels of the cognitive outcomes. RESULTS: Mean gestational 25(OH)D was 23.8 ng/mL (SD: 10.0 ng/mL). Each 10-ng/mL increase was associated with greater overall (β: 1.11; 95% CI: 0.08, 2.14) and fluid cognition scores (β: 1.21; 95% CI: 0.07, 2.34), but not crystallized cognition. Although these associations were not significantly modified by self-reported race, associations appeared stronger in children of Black mothers (β: 2.99; 95% CI: 0.82, 5.16) than those in non-Black mothers (β: 0.43; 95% CI: -0.93, 1.78) for fluid cognition. Early pregnancy may be a critical exposure period, evidenced by the greatest divergence in the pattern of 25(OH)D during this period between the mothers of children in the 90th and those in the 10th percentiles of cognitive outcomes. CONCLUSIONS: Gestational 25(OH)D concentrations were positively associated with cognitive scores, especially in children of Black mothers. Given higher deficiency risk among Black women, vitamin D repletion before or in early pregnancy may be an important strategy for reducing racial disparities in child neurodevelopment.

Humans↗

PubMed2025

Treatment response variations to a single large bolus of enteral cholecalciferol in vitamin D deficient critically Ill children: Metabolomic insights for precision nutrition.

Vitamin D deficiency (VDD) is prevalent globally and in pediatric intensive care units, where it represents a modifiable risk factor that may impact patient recovery during hospitalization. Herein, we performed a retrospective analysis of serum samples from a phase-II randomized placebo-controlled trial involving a single large bolus of 10,000 IU/kg vitamin D3 ingested by critically ill children with VDD (25-OH-D < 50 nmol/L). Targeted and untargeted methods were used to comprehensively measure 6 vitamin D metabolites, 239 lipids, 68 polar metabolites, and 4 electrolytes using a multi-step data workflow for compound authentication. Complementary statistical methods classified circulating metabolites/lipids associated with vitamin D repletion following high-dose vitamin D3 intake (n = 20) versus placebo (n = 11) comprising an optional standard of care maintenance dose (< 1000 IU/day). There was a striking increase in median serum concentrations of 25-OH-D3 (4.7-fold), 3-epi-25-OH-D3 (24-fold) and their C3-epimer ratio (6.7-fold) in treated patients on day 3, whereas serum vitamin D3 peaked on day 1 (128-fold) unlike placebo. Treatment response differences were attributed to D3 bioavailability and C3-epimerase activity without evidence of hypercalcemia. For the first time, we report the detection of circulating 3-epi-D3 that was strongly correlated with vitamin D3 uptake (r = 0.898). Metabolomic studies revealed that vitamin D sufficiency (serum 25-OH-D >75 nmol/L) coincided with lower circulating levels of 3-methylhistidine, cystine, S-methylcysteine, uric acid, and two lysophosphatidylcholines 7 days after treatment. Rapid correction of VDD was associated with indicators of lower oxidative stress, inflammation, and muscle protein turn-over that may contribute clinical benefits in high-risk critically ill children.

Humans↗

PubMed2026

Vitamin D Pathway Activation Reduces Cardiomyocyte DNA Damage and Improves Cardiac Contractility in Preclinical Models.

BACKGROUND: In heart failure (HF), DNA damage caused by various external stressors contributes to cardiac dysfunction through the activation of DNA damage response pathways. To date, no clinical strategies have been established to restore cardiac function by reducing accumulated DNA damage. We previously found that vitamin D improved contractility in lamin A/C (LMNA) p.Q353R-mutant induced pluripotent stem (iPS) cell-derived cardiomyocytes (iPSCMs), but whether this effect extends to other LMNA variants and in vivo models remained uncertain. OBJECTIVES: The objective of the study was to evaluate the association of vitamin D pathway activation with cardiomyocyte phosphorylated histone H2AX (γH2AX) foci and contractile phenotypes in patient-derived iPSCMs and mouse models of HF. METHODS: iPS cell lines were generated from dilated cardiomyopathy patients carrying the LMNA p.R225X mutation, and the effects of vitamin D treatment on γH2AX foci and cardiomyocyte contractility were evaluated. In addition, the effects of the vitamin D analog paricalcitol were evaluated in Lmna p.R225X mice and in a pressure overload mouse model of HF. RESULTS: Consistent with previous findings, vitamin D treatment reduced γH2AX foci in cardiomyocytes derived from LMNA p.R225X mutant iPS cells through upregulating the expression of DNA repair factors, and improved contractility in these iPSCMs. Furthermore, paricalcitol reduced γH2AX foci and attenuated cardiac dysfunction in both Lmna p.R225X mice and pressure overload HF model mice. CONCLUSIONS: Vitamin D pathway activation improved contractile phenotypes across complementary preclinical models and was accompanied by reduced γH2AX foci or related transcriptional changes. These findings support further mechanistic and preclinical investigation.

DNA damage↗

PubMed2026

Comparison of Traditional Chinese Exercise and Equipment-Based Exercise on Glycaemic Control and Vitamin D Levels in Middle-Aged and Elderly Patients With Prediabetes: A Randomised Controlled Trial.

BACKGROUND: Prediabetes is a critical window for preventing progression to type 2 diabetes mellitus (T2DM). Both vitamin D deficiency and physical inactivity are associated with impaired glucose metabolism. This study compared the effects of Traditional Chinese Exercise (TCE) and Kuanle Equipment Exercise (KEE) on glycaemic measures, lipid profiles, body composition and serum 25-hydroxyvitamin D3 [25(OH)D3] in middle-aged and elderly adults with prediabetes. METHODS: We conducted a 12-week, single-centre, randomised controlled trial involving 62 participants with prediabetes (mean age 55.2 ± 8.4 years; 88.7% female). Participants were randomly assigned to control (usual care, n = 21), TCE (n = 20), or KEE (n = 21). Primary outcomes included fasting plasma glucose (FPG), 2-h OGTT glucose, glycated haemoglobin (HbA1c) and serum 25(OH)D3. Secondary outcomes comprised triglycerides, total cholesterol, LDL-C, HDL-C and body composition. RESULTS: At baseline, mean serum 25(OH)D3 was 21.53 ± 3.90 nmol/L. At 12 weeks, both TCE and KEE improved FPG, 2-h OGTT glucose, HbA1c and 25(OH)D3 versus control (all p ≤ 0.001). Relative changes in FPG were -9.4% (TCE) and -15.2% (KEE) versus -1.5% (control); corresponding changes were -14.6% and -21.2% for 2-h OGTT glucose, -6.7% and -12.9% for HbA1c, and +60.6% and +81.9% for 25(OH)D3. Direct TCE-KEE comparisons were not significant (all p > 0.05). In an exploratory analysis, change in 25(OH)D3 was inversely associated with change in 2-h OGTT glucose (partial r = -0.358, p = 0.006), but not with FPG, HbA1c, or triglycerides. CONCLUSIONS: Both TCE and KEE improved glycaemic outcomes and increased serum 25(OH)D3 compared with usual care in middle-aged and elderly adults with prediabetes. Although KEE produced numerically larger estimates, direct between-group comparisons were not significant, and the superiority of KEE over TCE was not established. These vitamin D findings require confirmation in trials that quantify sunlight exposure and dietary vitamin D intake.

Aged↗

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↗

PubMed2025

The relationship between vitamin D levels and depression: a genetically informed study.

BACKGROUND: Low vitamin D (vitD) levels are consistently associated with an increased risk of depression. However, the biological mechanisms underlying this relationship and potential shared genetic overlap remain elusive. METHODS: We investigated the genetic overlap and causal relationships between depression (N = 589,356) and vitD levels (N = 417,580) using genome-wide association study (GWAS) summary statistics. We performed genome-wide and local genetic correlation analyses, followed by quantification of polygenic overlap variants. Shared genetic loci were identified and mapped to genes, which were further analyzed through gene expression and lifespan brain expression trajectory analyses. Bidirectional causal relationships were examined using multiple Mendelian randomization approaches. RESULTS: We observed significant negative genetic correlations (rg = -0.079) and identified genetic overlap (N = 410 variants). Genes mapped to the 13 shared loci showed opposing expression patterns. Tissue- and cell-specific functional enrichment analyses revealed significant signals related to brain development, with distinct patterns emerging between fetal development and adulthood. Shared genes (TRMT61A, ITIH4, RASGRP1, CTNND1, HERC1, IP6K1, FURIN ESR1, ZMYND and GRM5) exhibited notable expression variation in the brian throughout the lifespan, aligning with functional enrichment findings. CONCLUSIONS: Our findings elucidate the shared biological mechanisms underlying the relationship between vitD and depression, suggesting that vitD play an important role in the development of depression through altered early neurodevelopmental processes.

Humans↗

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↗

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↗

PubMed2022

Association of Vitamin D Polygenic Risk Scores and Disease Outcome in People With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Observational studies suggest low levels of 25-hydroxyvitamin D (25[OH]D) may be associated with increased disease activity in people with multiple sclerosis (PwMS). Large-scale genome-wide association studies (GWAS) suggest 25(OH)D levels are partly genetically determined. The resultant polygenic scores (PGSs) could serve as a proxy for 25(OH)D levels, minimizing potential confounding and reverse causation in analyses with outcomes. Herein, we assess the association of genetically determined 25(OH)D and disease outcomes in MS. METHODS: We generated 25(OH)D PGS for 1,924 PwMS with available genotyping data pooled from 3 studies: the CombiRx trial (n = 575), Johns Hopkins MS Center (n = 1,152), and Immune-Mediated Inflammatory Diseases study (n = 197). 25(OH)D-PGS were derived using summary statistics (p < 5 × 10-8) from a large GWAS including 485,762 individuals with circulating 25(OH)D levels measured. We included clinical and imaging outcomes: Expanded disability status scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), radiologic activity, and optical coherence tomography-derived ganglion cell inner plexiform layer (GCIPL) thickness. A subset (n = 935) had measured circulating 25(OH)D levels. We fitted multivariable models based on the outcome of interest and pooled results across studies using random effects meta-analysis. Sensitivity analyses included a modified p value threshold for inclusion in the PGS (5 × 10-5) and applying Mendelian randomization (MR) rather than using PGS. RESULTS: Initial analyses demonstrated a positive association between generated 25(OH)D-PGS and circulating 25(OH)D levels (per 1SD increase in 25[OH]D PGS: 3.08%, 95% CI: 1.77%, 4.42%; p = 4.33e-06; R2 = 2.24%). In analyses with outcomes, we did not observe an association between 25(OH)D-PGS and relapse rate (per 1SD increase in 25[OH]D-PGS: 0.98; 95% CI: 0.87-1.10), EDSS worsening (per 1SD: 1.05; 95% CI: 0.87-1.28), change in T25FW (per 1SD: 0.07%; 95% CI: -0.34 to 0.49), or change in 9HPT (per 1SD: 0.09%; 95% CI: -0.15 to 0.33). 25(OH)D-PGS was not associated with new lesion accrual, lesion volume or other imaging-based outcomes (whole brain, gray, white matter volume loss or GCIPL thinning). The results were similarly null in analyses using other p value thresholds or those applying MR. DISCUSSION: Genetically determined lower 25(OH)D levels were not associated with worse disease outcomes in PwMS and raises questions about the plausibility of a treatment effect of vitamin D in established MS.

Humans↗

PubMed2025

Short-term diet intervention comprising of olive oil, vitamin D, and omega-3 fatty acids alters the small non-coding RNA (sncRNA) landscape of human sperm.

Offspring health outcomes are often linked with epigenetic alterations triggered by maternal nutrition and intrauterine environment. Strong experimental data also link paternal preconception nutrition with pathophysiology in the offspring, but the mechanism(s) routing effects of paternal exposures remain elusive. Animal experimental models have highlighted small non-coding RNAs (sncRNAs) as potential regulators of paternal effects. Here, we characterised the baseline sncRNA landscape of human sperm and the effect of a 6-week dietary intervention on their expression profile. This study involves sncRNAseq profiling, that was performed on a subset (n = 17) of the participants enrolled in the PREPARE trial: 9 from the control group and 8 from the intervention group. 5'tRFs, miRNAs and piRNAs were the most abundant sncRNA subtypes identified; their expression was associated with age, BMI, and sperm quality. Nutritional intervention with olive oil, vitamin D and omega-3 fatty acids altered expression of 3 tRFs, 15 miRNAs and 112 piRNAs, targeting genes involved in fatty acid metabolism and transposable elements in the sperm genome. PREPARE Trial registration number: ISRCTN50956936, Trial registration date: 10/02/2014.

Humans↗