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FokI polymorphism in vitamin D receptor gene: Differential expression of TNF? in peripheral mononuclear cells of type 2 diabetic subjects.

ABSTRACT: Introduction:FokI polymorphism has been associated with obesity and type 2 diabetes (T2D) in some populations. Objective:To investigate the frequencies of a genetic polymorphism of Vitamin D receptor (FokI) in patients with T2D and control subjects and investigate the role of 1,25(OH)2D3 in the expression of pro-inflammatory markers in peripheral blood mononuclear cells (PBMCs). Methods:The case-control study was conducted in 160 patients with T2D and 160 control subjects, men and women (30-74 years old). The genotype and allele frequency of FokI polymorphisms were determined in these subjects. Subsequently a subgroup of 40 subjects was included from which PBMCs were removed. In vitro, the culture medium was supplemented with two different concentrations of 1,25(OH)2D3(10- 8 M and 10- 10 M). The expression profiles of TNF? and mRNA were analysed by qPCR, and GAPDH and ?-actin were used as housekeeping genes. Results:The control subjects have an increased frequency of the FF genotype. In subjects with T2D, the ff genotype was associated with higher HOMA-IR values than individuals with genotype Ff (p = 0.021). In vitro study in PBMCs showed differential expression of TNF? mRNA by FokI genotype, with a lower expression of this marker of inflammation in FF genotype subjects at a concentration of 10- 8 M of 1,25(OH)2D3. Conclusion:Our data suggest that VDR FokI polymorphism is associated with T2D, and the genotypes Ff and ff of this variant show a reduced response or resistance to the anti-inflammatory action of VitD, which could indicate a functional role of FokI polymorphism of VDR.

SUBMITTER: Angel B

PROVIDER: S-EPMC5963422 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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<i>FokI</i> polymorphism in vitamin D receptor gene: Differential expression of TNFα in peripheral mononuclear cells of type 2 diabetic subjects.

Angel Bárbara B Lera Lydia L Sánchez Hugo H Oyarzún Amaya A Albala Cecilia C

Meta gene 20151027

<h4>Introduction</h4><i>FokI</i> polymorphism has been associated with obesity and type 2 diabetes (T2D) in some populations.<h4>Objective</h4>To investigate the frequencies of a genetic polymorphism of Vitamin D receptor (<i>FokI</i>) in patients with T2D and control subjects and investigate the role of 1,25(OH)<sub>2</sub>D<sub>3</sub> in the expression of pro-inflammatory markers in peripheral blood mononuclear cells (PBMCs).<h4>Methods</h4>The case-control study was conducted in 160 patients ...[more]

PMID: 30941281

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Project description:The FokI vitamin D receptor (VDR) polymorphism results in different translation initiation sites on VDR. In the VDRff variant, initiation of translation occurs at the first ATG site, giving rise to a full length VDR protein of 427 amino acids. Conversely, in the VDRFF variant, translation begins at the second ATG site, resulting in a truncated protein with three less amino acids. Epidemiological studies have paradoxically implicated this polymorphism with increased breast cancer risk. 1?,25 (OH)(2)D(3), the active metabolite of vitamin D, is known to inhibit cell proliferation, induce apoptosis and potentiate differentiation in human breast cancer cells. It is well documented that 1?,25 (OH)(2)D(3) downregulates estrogen receptor ? expression and inhibits estrogen mediated signaling in these cells. The functional significance of the VDR FokI polymorphism in vitamin D action is undefined.To elucidate the functional role of FokI polymorphism in breast cancer, MCF-7-Vector, MCF-7-VDRff and MCF-7-VDRFF stable cell lines were established from parental MCF-7 cells as single-cell clones. In response to 1?,25 (OH)(2)D(3) treatments, cell growth was inhibited by 60% in VDRFF cells compared to 28% in VDRff cells. The induction of the vitamin D target gene CYP24A1 mRNA was 1.8 fold higher in VDRFF cells than in VDRff cells. Estrogen receptor-? protein expression was downregulated by 62% in VDRFF cells compared to 25% in VDRff cells. VDR protein stability was greater in MCF-7-VDRFF cells in the presence of cycloheximide. PCR array analyses of VDRff and VDRFF cells revealed increased basal expression levels of pro-inflammatory genes Cyclooxygenase-2, Interleukin-8 and Chemokine (C-C Motif) Ligand 2 in MCF-7-VDRff cells by 14, 52.7 and 5 fold, respectively.These results suggest that a VDRff genotype may play a role in amplifying aggressive breast cancer, paving the way for understanding why some breast cancer cells respond inefficiently to vitamin D treatment.

Dataset Information

FokI polymorphism in vitamin D receptor gene: Differential expression of TNF? in peripheral mononuclear cells of type 2 diabetic subjects.

Publications

<i>FokI</i> polymorphism in vitamin D receptor gene: Differential expression of TNFα in peripheral mononuclear cells of type 2 diabetic subjects.

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