Vitamin D receptor gene BsmI, FokI, ApaI and TaqI polymorphisms and the risk of systemic lupus erythematosus

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Abstract

Recently, several studies have demonstrated the role of vitamin D receptor ( VDR) polymorphisms in the development of systemic lupus erythematosus (SLE); however, these results are inconsistent between different cohorts. Therefore, we studied the prevalence of the VDR FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236) genotypes and alleles in SLE patients ( n = 258) and healthy individuals ( n = 545) in a Polish population. We did not observe significant differences for either the VDR FokI, BsmI, ApaI and TaqI genotype and allele frequencies in patients with SLE and healthy individuals. However, the frequency of the VDR F/F and F/f genotypes of FokI was statistically different between patients with renal disease and patients without this symptom OR = 3.228 (1.534–6.792, p = 0.0014), p _corr = 0.0476)]. There was no association of the studied VDR BsmI, ApaI and TaqI polymorphisms with clinical manifestations and laboratory profiles in patients with SLE. Our study indicates that the studied VDR FokI variant might increase the risk of some clinical presentations in patients with SLE.

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Most cited references 38

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Genetics and biology of vitamin D receptor polymorphisms.

André G. Uitterlinden, Yue Fang, Joyce B J van Meurs … (2004)

The vitamin D endocrine system is involved in a wide variety of biological processes including bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation. Variations in this endocrine system have, thus, been linked to several common diseases, including osteoarthritis (OA), diabetes, cancer, cardiovascular disease, and tuberculosis. Evidence to support this pleiotropic character of vitamin D has included epidemiological studies on circulating vitamin D hormone levels, but also genetic epidemiological studies. Genetic studies provide excellent opportunities to link molecular insights with epidemiological data and have therefore gained much interest. DNA sequence variations, which occur frequently in the population, are referred to as "polymorphisms" and can have modest and subtle but true biological effects. Their abundance in the human genome as well as their high frequencies in the human population have made them targets to explain variation in risk of common diseases. Recent studies have indicated many polymorphisms to exist in the vitamin D receptor (VDR) gene, but the influence of VDR gene polymorphisms on VDR protein function and signaling is largely unknown. So far, three adjacent restriction fragment length polymorphisms for BsmI, ApaI, and TaqI, respectively, at the 3' end of the VDR gene have been the most frequently studied. Because these polymorphisms are probably nonfunctional, linkage disequilibrium with one or more truly functional polymorphisms elsewhere in the VDR gene is assumed to explain the associations observed. Research is therefore focussed on documenting additional polymorphisms across the VDR gene to verify this hypothesis and on trying to understand the functional consequences of the variations. Substantial progress has been made that will deepen our understanding of variability in the vitamin D endocrine system and might find applications in risk assessment of disease and in predicting response-to-treatment.

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1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation.

G Penna, L Adorini (2000)

1 Alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D3, is a potent immunomodulatory agent. Here we show that dendritic cells (DCs) are major targets of 1,25(OH)2D3-induced immunosuppressive activity. 1,25(OH)2D3 prevents the differentiation in immature DCs of human monocytes cultured with GM-CSF and IL-4. Addition of 1,25(OH)2D3 during LPS-induced maturation maintains the immature DC phenotype characterized by high mannose receptor and low CD83 expression and markedly inhibits up-regulation of the costimulatory molecules CD40, CD80, and CD86 and of class II MHC molecules. This is associated with a reduced capacity of DCs to activate alloreactive T cells, as determined by decreased proliferation and IFN-gamma secretion in mixed leukocyte cultures. 1, 25(OH)2D3 also affects maturing DCs, leading to inhibition of IL-12p75 and enhanced IL-10 secretion upon activation by CD40 ligation. In addition, 1,25(OH)2D3 promotes the spontaneous apoptosis of mature DCs. The modulation of phenotype and function of DCs matured in the presence of 1,25(OH)2D3 induces cocultured alloreactive CD4+ cells to secrete less IFN-gamma upon restimulation, up-regulate CD152, and down-regulate CD154 molecules. The inhibition of DC differentiation and maturation as well as modulation of their activation and survival leading to T cell hyporesponsiveness may explain the immunosuppressive activity of 1, 25(OH)2D3.

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A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women.

T Tonai, H. Arai, Hiroshi Yamamoto … (1997)

The effect of a T-C transition polymorphism at the translation initiation codon of the human vitamin D receptor (VDR) gene on the biological function of the encoded protein was investigated. Of 239 Japanese women volunteers subjected to genotype analysis for this polymorphism, 32 (13%) were genotype MM (the M allele is ATG at the putative translation start site), 75 (31%) were genotype mm (the m allele is ACG at the putative translation start site), and 132 (55%) were genotype Mm. The bone mineral density (BMD) in the lumbar spine (L2-L4) was determined for 110 healthy premenopausal women from the volunteers and was shown to be 12.0% greater (p < 0.05) for mm homozygotes than for MM homozygotes. Synthesis of the proteins by the M and m alleles from the cloned cDNAs in vitro and in transfected COS-7 cells revealed them to have a size of 50 and 49.5 kD, respectively, as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. This size difference is consistent with initiation of translation of the M allele-encoded protein from an ATG codon located at nucleotides +10 to +12 in the conventional open reading frame. The extent of vitamin D-dependent transcriptional activation of a reporter construct under the control of a vitamin D response element in transfected HeLa cells was approximately 1.7-fold greater for the m type VDR than for the M type protein. These results suggest that the polymorphism at the translation start site of the VDR gene may modulate BMD in premenopausal Japanese women.

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Author and article information

Contributors

: +48 61-854-6510 , pjagodzi@am.poznan.pl

Journal

Journal ID (nlm-ta): Mol Biol Rep

Journal ID (iso-abbrev): Mol. Biol. Rep

Title: Molecular Biology Reports

Publisher: Springer Netherlands (Dordrecht )

ISSN (Print): 0301-4851

ISSN (Electronic): 1573-4978

Publication date (Electronic): 14 October 2012

Publication date PMC-release: 14 October 2012

Publication date (Print): February 2013

Volume: 40

Issue: 2

Pages: 803-810

Affiliations

[ ]Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, 6 Święcickiego St, 60-781 Poznan, Poland

[ ]Institute of Rheumatology, Warsaw, Poland

Article

Publisher ID: 2118

DOI: 10.1007/s11033-012-2118-6

PMC ID: 3538008

PubMed ID: 23065277

SO-VID: 56bc5d14-ad39-47cb-8c54-4efe6885b35f

History

Date received : 7 June 2012

Date accepted : 3 October 2012

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ScienceOpen disciplines: Molecular biology

Keywords: vdr polymorphism,sle,pcr–rflp

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ScienceOpen disciplines: Molecular biology

Keywords: vdr polymorphism, sle, pcr–rflp

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Vitamin D receptor gene BsmI, FokI, ApaI and TaqI polymorphisms and the risk of systemic lupus erythematosus

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Most cited references 38

Genetics and biology of vitamin D receptor polymorphisms.

1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation.

A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women.

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