Association between vitamin D receptor (<i>VDR</i>) gene polymorphisms and systemic lupus erythematosus in Portuguese patients

Carvalho, Cláudia; Marinho, António; Leal, Bárbara; Bettencourt, Andreia; Boleixa, Daniela; Almeida, Isabel; Farinha, Fátima; Costa, Paulo; Vasconcelos, Carlos; Silva, Ana Martins

doi:10.1177/0961203314566636

Cited by 75 publications

(68 citation statements)

References 42 publications

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“…For this reason, genetic variation in the VDR gene changing its binding affinity, activity or protein levels may influence the immunological efficiency of vitamin D. In addition, in vitro and knock-out mice experiments have linked VDR to the resistance to Leishmania major infection 32 . Indeed, genetic variants in the VDR gene have also been associated with an increased risk of chronic chagasic cardiomyopathy 51 , malaria severity 52 , tuberculosis 53 , and some autoimmune disorders 54, 55 . Our results showed that the four VDR polymorphisms display similar frequencies across the non-infected, asymptomatic, and symptomatic dog groups (Table 3), and no genetic association between these SNPs and disease/infection status were observed (Table 4).…”

Section: Discussionmentioning

confidence: 99%

Canine Leishmaniasis Progression is Associated with Vitamin D Deficiency

Rodríguez-Cortés

Martori

Martínez-Flórez

et al. 2017

Sci Rep

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The relationship between vitamin D deficiency and the risk of suffering from a plethora of health disorders, ranging from autoimmune processes to infectious diseases has been widely described. Nonetheless, the potential role of vitamin D in visceral leishmaniasis remains uncharacterized. In the Mediterranean basin, where the dog is leishmania’s main peri-domestic reservoir, control measures against the canine disease have shown beneficial effects on the incidence of human leishmaniasis. In this study, we measured the vitamin D levels in serum samples from a cohort of 68 healthy and disease dogs from a highly endemic area and we have also studied the relationship of these levels with parasitological and immunological parameters. The sick dogs presented significantly lower (P < 0.001) vitamin D levels (19.6 ng/mL) than their non-infected (31.8 ng/mL) and the asymptomatic counterparts (29.6 ng/mL). In addition, vitamin D deficiency correlated with several parameters linked to leishmaniasis progression. However, there was no correlation between vitamin D levels and the Leishmania-specific cellular immune response. Moreover, both the leishmanin skin test and the IFN-γ levels displayed negative correlations with serological, parasitological and clinical signs. Further studies to determine the functional role of vitamin D on the progression and control of canine leishmaniasis are needed.

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Section: Discussionmentioning

confidence: 99%

Canine Leishmaniasis Progression is Associated with Vitamin D Deficiency

Rodríguez-Cortés

Martori

Martínez-Flórez

et al. 2017

Sci Rep

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“…Ozaki et al [31] reported BsmI polymorphisms in 58 Japanese SLE patients; their findings revealed that the BB genotype might trigger the development of lupus and the bb genotype was associated with lupus nephritis. Carvalho et al [32] suggested a possible role of VDR gene polymorphisms in Portuguese patients with SLE as a positive association was found between VDR gene variants and lupus severity (chronic damage).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D receptor gene BsmI polymorphisms in Egyptian children and adolescents with systemic lupus erythematosus

et al. 2016

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Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease. The vitamin D receptor (VDR) gene is a candidate gene for susceptibility to autoimmune disorders. To date, only a few studies concerned the association of the VDR gene polymorphisms with childhood-onset SLE.In this study, we aimed to investigate the BsmI polymorphisms in the VDR gene, for the first time in Egyptian children and adolescents with SLE, to determine whether this polymorphism could be a marker of susceptibility to or severity of SLE and we also measured the serum level of 25-hydroxyvitamin D (25[OH] D) to assess its relation to such polymorphism.This was a case–control study including 100 patients with SLE and matched with age, sex, and ethnicity and 100 healthy controls. All subjects were genotyped for the VDR gene BsmI polymorphism by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), whereas the serum 25(OH) D levels were measured by enzyme-linked immunosorbent assay method.Compared to the contros subjects, the VDR BsmI BB genotype and B allele were overrepresented among SLE patients (odda ratio [OR]: 5.5; 95% confidence interval [CI]: 1.9–15.9; P = 0.002 and OR: 1.84; 95% CI: 1.21–2.80; P = 0.003; respectively). We found a significant association between VDR BsmI BB genotype with lupus nephritis (OR: 6.8; 95% CI: 1.18–50.5; P = 0.001). However, we did not observe any significant association of studied polymorphisms with other clinical manifestations, laboratory profiles of SLE, or disease activity score. Our data revealed no association between VDR BsmI genotypes or alleles and serum 25-hydroxyvitamin D levels among studied patients with SLE (all P > 0.05).We demonstrate for the first time, to the best of our knowledge, that the VDR BsmI gene polymorphisms may contribute to susceptibility to SLE in Egyptian children and adolescents. Moreover, we found that the BB genotype constituted a risk factor for the development of nephropathy among studied patients with SLE. However, we did not find any significant association of the VDR BsmI gene variants with other clinical manifestations, laboratory profiles of SLE, disease activity index score, or serum 25-hydroxyvitamin D levels.

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“…It was also found that 1,25(OH) 2 D 3 could regulate the expression of many apoptosis factors or mediators and directly induce apoptosis through the activation of Caspase, which had been proved that it could reduce the immunostimulatory effects of the SLE [24,25]. Carvalho et al had illustrated vitamin D, acting through VDR expressed in all immune cells, played an important role in the immune system homeostasis, and VDR polymorphisms and SLE had positive association [26]. In addition, some immunosuppressive effects were mediated by the interaction of hormone and nuclear receptor, and it had found that VDR could regulate gene expressions of sensitive tissues in vitamin D [27], which was consistent with our results.…”

Section: Discussionmentioning

confidence: 99%

Roles of 1,25(OH)2D3 and Vitamin D Receptor in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus by Regulating the Activation of CD4+ T Cells and the PKCδ/ERK Signaling Pathway

Ding²,

Xiang³

et al. 2016

Cell Physiol Biochem

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Background/Aims: The study aims to elucidate the roles of 1,25(OH)₂D₃ and vitamin D receptor (VDR) in the pathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) by regulating the activation of CD4⁺ T cells and the PKCδ/ERK signaling pathway. Methods: From January 2013 to December 2015, a total of 130 SLE patients, 137 RA patients and 130 healthy controls were selected in this study. Serum levels of 1,25(OH)₂D₃ and VDR mRNA expression were detected by ELISA and real-time fluorescence quantitative PCR (RT-qPCR). Density gradient centrifugation was performed to separate peripheral blood mononuclear cells (PBMCs). CD4⁺ T cells were separated using magnetic activated cell sorting (MACS). CD4⁺T cells in logarithmic growth phase were collected and assigned into 9 groups: the normal control group, the normal negative control (NC) group, the VDR siRNA group, the RA control group, the RA NC group, the VDR over-expressed RA group, the SLE control group, the SLE NC group, and the VDR over-expressed SLE group. The mRNA and protein expressions of VDR, PKCδ, ERK1/2, CD11a, CD70 and CD40L were detected by RT-qPCR and Western blotting. Bisulfite genomic sequencing was conducted to monitor the methylation status of CD11a, CD70 and CD40L. Results: Compared with healthy controls, serum 1,25(OH)₂D₃ level and VDR mRNA expression in peripheral blood were decreased in SLE patients and RA patients. With the increase of concentrations of 1,25(OH)₂D₃ treatment, the VDR mRNA expression and DNA methylation levels of CD11a, CD70 and CD40L were declined, while the expressions of PKCδ, ERK1/2, CD11a, CD70 and CD40L were elevated in SLE, RA and normal CD4⁺T cells. Compared with the SLE contro, RA control, SLE NC and RA NC groups, the expressions of PKCδ, ERK1/2, CD11a, CD70 and CD40L decreased but DNA methylation levels of CD11a, CD70 and CD40L increased in the VDR over-expressed SLE group and VDR over-expressed RA group. However, compared with the normal control and normal NC groups, the expressions of PKCδ, ERK1/2, CD11a, CD70 and CD40L increased, but DNA methylation levels of CD11a, CD70 and CD40L decreased in the VDR siRNA group. Compared with the normal control group, the expressions of PKCδ, ERK1/2, CD11a, CD70 and CD40L increased, but DNA methylation levels of CD11a, CD70 and CD40L decreased in the SLE control and RA control groups. Conclusion: Our study provide evidence that 1,25(OH)₂D₃ and VDR could inhibit the activation of CD4⁺ T cells and suppress the immune response of SLE and RA through inhibiting PKCδ/ERK pathway and promoting DNA methylation of CD11a, CD70 and CD40L.

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Association between vitamin D receptor (VDR) gene polymorphisms and systemic lupus erythematosus in Portuguese patients

Cited by 75 publications

References 42 publications

Canine Leishmaniasis Progression is Associated with Vitamin D Deficiency

Canine Leishmaniasis Progression is Associated with Vitamin D Deficiency

Vitamin D receptor gene BsmI polymorphisms in Egyptian children and adolescents with systemic lupus erythematosus

Roles of 1,25(OH)2D3 and Vitamin D Receptor in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus by Regulating the Activation of CD4+ T Cells and the PKCδ/ERK Signaling Pathway

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