Methylation of the Vitamin D Receptor (VDR) Gene, Together with Genetic Variation, Race, and Environment Influence the Signaling Efficacy of the Toll-Like Receptor 2/1-VDR Pathway

Meyer, Vanessa; Saccone, Donovan Sean; Tugizimana, Fidele; Asani, Furaha Florence; Jeffery, Tamsyn Jacki; Bornman, Liza

doi:10.3389/fimmu.2017.01048

Cited by 31 publications

(34 citation statements)

References 47 publications

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“…The SNP selection was determined by their relationship with vitamin D concentrations in pregnant women and its association with neonatal outcomes (Barchitta et al, ; Knabl et al, ). TaqI and ApaI are highly prevalent in populations with African ancestry (Meyer, et al, ), similar to the sample of this study (Lima‐Costa et al, )…”

Section: Methodssupporting

confidence: 87%

Polymorphism in the vitamin D receptor gene is associated with maternal vitamin D concentration and neonatal outcomes: A Brazilian cohort study

Pereira

Carvalho

Louro

et al. 2019

American J Hum Biol

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Objectives: This study evaluated the associations between single-nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene, maternal vitamin D concentration, and gestational outcomes. Methods: The cohort consisted of 270 pregnant women who received prenatal services at basic public healthcare centers in the city of Santo Antônio de Jesus, Bahia, Brazil. For statistical analysis, multiple linear regression was used. Results: A mean of 72.62 (SD = 31.51) nmol/L for 25-hydroxyvitamin D (25(OH) D) concentrations was found. The mean birth weight was 3.340 g (SD = 0.545 g), and the mean duration of gestation was 38.66 (SD = 1.83) weeks. Pregnant women who were homozygous for the low-frequency allele GG of SNP TaqI had a higher concentration of vitamin D during gestation (β = 14.09 nmol/L; 95% CI = 0.85, 27.34) than the higher frequency homozygotes AA (β = 3.33 nmol/L; 95% CI = −4.37, 11.05). The children of heterozygous women for the ApaI SNP (GA) were born with a lower weight (β = −131.99 g, 95% CI = −258.50, −5.47, P = .04). The heterozygote genotype of the SNP TaqI (CA) decreased the risk of short duration of gestation (β = 0.54 weeks, 95% CI = 0.09, 0.99, P = .01), and the homozygote for the lower frequency allele in the SNP ApaI (CC) showed a negative effect, decreasing the duration of gestation (β = −0.69 weeks, 95% CI = −1.35, −0.26, P = .04). Conclusions: The VDR gene is an important genetic predictor of a higher concentration of vitamin D during gestation, low birth weight, and decreasing duration of gestation.

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Section: Methodssupporting

confidence: 87%

Polymorphism in the vitamin D receptor gene is associated with maternal vitamin D concentration and neonatal outcomes: A Brazilian cohort study

Pereira

Carvalho

Louro

et al. 2019

American J Hum Biol

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“…CYP27B1 catalyzes the de novo production of 1,25(OH) 2 D from accumulated 25(OH)D; 1,25(OH) 2 D is delivered to the cells via the vitamin D-binding protein (DBP), which is encoded by GC. The liganded VDR-transcription factor complex binds to vitamin D response elements (VDREs) in cathelicidin antimicrobial peptide (CAMP), activating CAMP expression [ 45 ]. The methylation level of CYP27B1 is elevated in primary lymphoma and leukemia cells [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

“…Whether this subtle methylation difference could alter vitamin D metabolism and change macrophage M.tb killing capacity is not clear and needs more exploration. Other factors, such as genetic polymorphisms, sunlight exposure, food intake, and drug supplementation, can also affect vitamin D levels and the risk of TB [ 45 ]. Third, immune responses downstream of the vitamin D metabolic pathway should also be considered.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D and the promoter methylation of its metabolic pathway genes in association with the risk and prognosis of tuberculosis

Wang

Kong

et al. 2018

Clin Epigenet

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BackgroundA variety of abnormalities in vitamin D metabolism have been reported in patients with active tuberculosis. However, intervention trials have produced inconsistent results. We hypothesized that genetic and epigenetic changes in the key genes of the vitamin D metabolic pathway may partly explain the differences between studies.MethodsWe performed a case-control study followed by a prospective cohort study. We recruited 122 patients with pulmonary tuberculosis and 118 healthy controls. The serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were measured. The methylation of the promoter regions of key genes in the vitamin D metabolic pathway (CYP24A1, CYP27A1, CYP27B1, CYP2R1, and VDR) was detected using the Illumina MiSeq platform. The specific methylation profiles were examined as epigenetic biomarkers. The sensitivity, specificity, and receiver operating characteristic (ROC) curves were used to estimate the predictive value of the biomarkers.ResultsThe baseline serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations in the cases were significantly lower than those in the controls (51.60 ± 27.25 nmol/L vs. 117.50 ± 75.50 nmol/L, Z = − 8.515, P < 0.001; 82.63 ± 51.43 pmol/L vs. 94.02 ± 49.26 pmol/L, Z = − 2.165, P = 0.03). We sequenced 310 CpG sites in five candidate genes. After Bonferroni correction, there were 55 differentially methylated CpG sites between cases and controls; 41.5% were in the CYP27B1 gene, 31.7% were in the CYP24A1 gene, 14.7% were in the VDR gene, and 12.3% were in the CYP27A1 gene. When we designated the CpG sites that remained significant after the Bonferroni correction as the biomarkers, the area under the curve (AUC) for the cumulative methylation was 0.810 (95% CI 0.754–0.866). There was an interaction between CYP27A1 methylation level and 1,25-dihydroxyvitamin D concentration associated with the risk of TB (ORinteraction = 4.11, 95% CI 1.26–13.36, P = 0.019). The serum 1,25-dihydroxyvitamin D concentration at the end of the intensive treatment stage was related to a patient’s prognosis (P = 0.008). There were 23 CpG sites that were individually related to the treatment outcomes, but the relationships were not significant after the Bonferroni correction.ConclusionBoth serum vitamin D concentrations and the methylation levels of key genes in the vitamin D metabolic pathway are related to the risk and prognosis of tuberculosis.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0552-6) contains supplementary material, which is available to authorized users.

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“…27,28 Several studies have suggested that VDR gene methylation alterations may have a role in the pathogenesis of infectious and malignant diseases. [29][30][31][32][33][34] Vitamin D plays an important regulatory role in immune system 6 function and its deficiency has been introduced in the etiology of autoimmune diseases. 19,35 It affects many aspects of the innate and adaptive immune system.…”

Section: Introductionmentioning

confidence: 99%

The expression and methylation status of vitamin D receptor gene in Behcet's disease

Shirvani

Nouri

Sakhinia

et al. 2019

Immunity Inflam & Disease

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Introduction Vitamin D has important roles as a natural immune modulator via regulating the expression of genes which have been implicated in the pathophysiology of autoimmune diseases. Vitamin D function and its deficiency have been linked to a wide range of metabolic disorders including disorders of calcium metabolism, malignant, cardiovascular, infectious, neuromuscular, and inflammatory diseases. Environmental factors, genetic factors, and epigenetic changes contribute to Behcet's disease (BD) development. The aim of our study was to analyze the expression level and methylation status of the vitamin D receptor (VDR) gene promoter in the peripheral blood mononuclear cells (PBMCs) of patients with BD. Methods In a case‐control study, 48 Iranian Azeri patients with BD and 60 age‐, sex‐ and ethnically‐matched healthy controls were included. Venous blood samples were collected and PBMCs were isolated by Ficoll protocol. The DNA and RNA were subsequently extracted. Promoter methylation levels were evaluated by MeDIP‐quantitative polymerase chain reaction (qPCR). The expression of VDR was evaluated by real‐time PCR. Results The results of quantitative real‐time PCR analysis showed that the level of VDR expression in patients with BD was significantly lower than the control group (P = .013). There was no significant difference in the level of DNA methylation in the BD and control groups (P > .05). As the results show, the expression level of VDR gene was significantly different between female and male in the patient group (P = .001). VDR gene expression was significantly higher in subjects with phlebitis. No correlation was observed between VDR gene expression rate and BD activity. Conclusion VDR gene expression decreased in patients with BD. However, there is no suggestion evidence that the expression level of VDR is regulated by a unique DNA methylation mechanism. No correlation exists between VDR gene expression and BD activity.

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Methylation of the Vitamin D Receptor (VDR) Gene, Together with Genetic Variation, Race, and Environment Influence the Signaling Efficacy of the Toll-Like Receptor 2/1-VDR Pathway

Cited by 31 publications

References 47 publications

Polymorphism in the vitamin D receptor gene is associated with maternal vitamin D concentration and neonatal outcomes: A Brazilian cohort study

Polymorphism in the vitamin D receptor gene is associated with maternal vitamin D concentration and neonatal outcomes: A Brazilian cohort study

Vitamin D and the promoter methylation of its metabolic pathway genes in association with the risk and prognosis of tuberculosis

The expression and methylation status of vitamin D receptor gene in Behcet's disease

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