Skip to main content

Advertisement

SpringerLink
Log in

Vitamin D and polymorphisms of VDR gene in patients with systemic lupus erythematosus

  • Review Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

The susceptibility for the development of systemic lupus erythematosus (SLE) is related to environmental, hormonal, genetic, and immunological factors. Numerous genes have been linked to the emergence of SLE, including vitamin D receptor (VDR) gene that synthesizes the receptor of vitamin D. Several polymorphisms have been described since the discovery of this gene, and their effects on VDR activity are still poorly understood. Vitamin D’s biological functions are mediated by VDR. Vitamin D exerts many actions on the immune system, and several studies have suggested its role in the pathogenesis of autoimmune diseases. SLE patients have low blood levels of vitamin D, which raises the possibility of association between the deficiency of this vitamin and the onset of the disease. BsmI and FokI polymorphic variants seem to be related to the onset of the disease in Asian patients. In this article, we review the aspects related to the metabolism and immunoregulatory effects of vitamin D, VDR, and main polymorphisms involving the VDR gene and the relationship between vitamin D levels and its receptor with SLE.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Oliveira NMP, Lemos MC (2010) Papel da vitamina D na susceptibilidade para a Diabetes Mellitus tipo 1. Dissertação de Mestrado Integrado em Medicina Universidade da Beira Interior, Covilha

    Google Scholar 

  2. DeLuca HF (2004) Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr 80(6 Suppl):1689S–1696S

    PubMed  CAS  Google Scholar 

  3. Holick MF (2007) Vitamin D deficiency. N Engl J Med 357(3):266–281

    Article  PubMed  CAS  Google Scholar 

  4. Premaor MO, Furlanetto TW (2006) Hipovitaminose D em adultos: entendendo melhor a apresentação de uma velha doença. Arquivos Brasileiros de Endocrinologia 50(1):25–37

    Article  Google Scholar 

  5. Valdivielso JM, Fernandez E (2006) Vitamin D receptor polymorphisms and diseases. Clin Chim Acta 371(1–2):1–12

    Article  PubMed  CAS  Google Scholar 

  6. Dusso AS, Brown AJ, Vitamin SE (2005) Vitamin D. Am J Physiol Renal Physiol 289(1):F8–F28

    Article  PubMed  CAS  Google Scholar 

  7. Takeyama K, Kitanaka S, Sato T, Kobori M, Yanagisawa J, Kato S (1997) 25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis. Science 277(5333):1827–1830

    Article  PubMed  CAS  Google Scholar 

  8. Kamen D, Aranow C (2008) Vitamin D in systemic lupus erythematosus. Curr Opin Rheumatol 20(5):532–537

    Article  PubMed  CAS  Google Scholar 

  9. Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R (2005) Estimates of optimal vitamin D status. Osteoporos Int 16(7):713–716

    Article  PubMed  CAS  Google Scholar 

  10. Bandeira F, Griz L, Dreyer P, Eufrazino C, Bandeira C, Freese E (2006) Vitamin D deficiency: a global perspective. Arq Bras Endocrinol Metabol 50(4):640–646

    Article  PubMed  Google Scholar 

  11. Holick MF (2006) High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 81(3):353–373

    Article  PubMed  CAS  Google Scholar 

  12. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B (2006) Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 84(1):18–28

    PubMed  CAS  Google Scholar 

  13. Malabanan A, Veronikis IE, Holick MF (1998) Redefining vitamin D insufficiency. Lancet 351(9105):805–806

    Article  PubMed  CAS  Google Scholar 

  14. Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT et al (1998) Hypovitaminosis D in medical inpatients. N Engl J Med 338(12):777–783

    Article  PubMed  CAS  Google Scholar 

  15. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK et al (2011) The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 96(1):53–58

    Article  PubMed  CAS  Google Scholar 

  16. Cantorna MT, Mahon BD (2004) Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med (Maywood) 229(11):1136–1142

    CAS  Google Scholar 

  17. Heaney RP, Holick MF (2011) Why the IOM recommendations for vitamin D are deficient. J Bone Miner Res 26(3):455–457

    Article  PubMed  CAS  Google Scholar 

  18. Slomski A (2011) IOM endorses vitamin D, calcium only for bone health, dispels deficiency claims. Jama 305(5):453–454, 6

    Article  PubMed  CAS  Google Scholar 

  19. Yamada S, Yamamoto K, Masuno H, Choi M (2001) Three-dimensional structure-function relationship of vitamin D and vitamin D receptor model. Steroids 66(3-5):177–187

    Article  PubMed  CAS  Google Scholar 

  20. Miyamoto K, Kesterson RA, Yamamoto H, Taketani Y, Nishiwaki E, Tatsumi S et al (1997) Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Mol Endocrinol 11(8):1165–1179

    Article  PubMed  CAS  Google Scholar 

  21. Durrin LK, Haile RW, Ingles SA, Coetzee GA (1999) Vitamin D receptor 3′-untranslated region polymorphisms: lack of effect on mRNA stability. Biochim Biophys Acta 1453(3):311–320

    Article  PubMed  CAS  Google Scholar 

  22. Decker CJ, Parker R (1995) Diversity of cytoplasmic functions for the 3' untranslated region of eukaryotic transcripts. Curr Opin Cell Biol 7(3):386–392

    Article  PubMed  CAS  Google Scholar 

  23. Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP (2004) Genetics and biology of vitamin D receptor polymorphisms. Gene 338(2):143–156

    Article  PubMed  CAS  Google Scholar 

  24. Morrison NA, Yeoman R, Kelly PJ, Eisman JA (1992) Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphism and circulating osteocalcin. Proc Natl Acad Sci USA 89(15):6665–6669

    Article  PubMed  CAS  Google Scholar 

  25. Faraco JH, Morrison NA, Baker A, Shine J, Frossard PM (1989) ApaI dimorphism at the human vitamin D receptor gene locus. Nucleic Acids Res 17(5):2150

    Article  PubMed  CAS  Google Scholar 

  26. Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV et al (1994) Prediction of bone density from vitamin D receptor alleles. Nature 367(6460):284–287

    Article  PubMed  CAS  Google Scholar 

  27. Arai H, Miyamoto K, Taketani Y, Yamamoto H, Iemori Y, Morita K et al (1997) A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women. J Bone Miner Res 12(6):915–921

    Article  PubMed  CAS  Google Scholar 

  28. Gross C, Eccleshall TR, Malloy PJ, Villa ML, Marcus R, Feldman D (1996) The presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal Mexican-American women. J Bone Miner Res 11(12):1850–1855

    Article  PubMed  CAS  Google Scholar 

  29. Jurutka PW, Remus LS, Whitfield GK, Thompson PD, Hsieh JC, Zitzer H et al (2000) The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB. Mol Endocrinol 14(3):401–420

    Article  PubMed  CAS  Google Scholar 

  30. Whitfield GK, Remus LS, Jurutka PW, Zitzer H, Oza AK, Dang HT et al (2001) Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene. Mol Cell Endocrinol 177(1–2):145–159

    Article  PubMed  CAS  Google Scholar 

  31. Colin EM, Weel AE, Uitterlinden AG, Buurman CJ, Birkenhager JC, Pols HA et al (2000) Consequences of vitamin D receptor gene polymorphisms for growth inhibition of cultured human peripheral blood mononuclear cells by 1, 25-dihydroxyvitamin D3. Clin Endocrinol (Oxf) 52(2):211–216

    Article  CAS  Google Scholar 

  32. van Etten E, Verlinden L, Giulietti A, Ramos-Lopez E, Branisteanu DD, Ferreira GB et al (2007) The vitamin D receptor gene FokI polymorphism: functional impact on the immune system. Eur J Immunol 37(2):395–405

    Article  PubMed  Google Scholar 

  33. Trinchieri G, Sher A (2007) Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 7(3):179–190

    Article  PubMed  CAS  Google Scholar 

  34. Ramanathan B, Davis EG, Ross CR, Blecha F (2002) Cathelicidins: microbicidal activity, mechanisms of action, and roles in innate immunity. Microbes Infect 4(3):361–372

    Article  PubMed  CAS  Google Scholar 

  35. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J et al (2004) Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 173(5):2909–2912

    PubMed  CAS  Google Scholar 

  36. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR et al (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311(5768):1770–1773

    Article  PubMed  CAS  Google Scholar 

  37. Arnson Y, Amital H, Shoenfeld Y (2007) Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis 66(9):1137–1142

    Article  PubMed  CAS  Google Scholar 

  38. Deluca HF, Cantorna MT (2001) Vitamin D: its role and uses in immunology. Faseb J 15(14):2579–2585

    Article  PubMed  CAS  Google Scholar 

  39. Kamen DL, Tangpricha V (2010) Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med 88(5):441–450

    Article  PubMed  CAS  Google Scholar 

  40. Griffin MD, Lutz W, Phan VA, Bachman LA, McKean DJ, Kumar R (2001) Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci USA 98(12):6800–6805

    Article  PubMed  CAS  Google Scholar 

  41. Lanzavecchia A, Sallusto F (2001) Regulation of T cell immunity by dendritic cells. Cell 106(3):263–266

    Article  PubMed  CAS  Google Scholar 

  42. O'Regan S, Chesney RW, Hamstra A, Eisman JA, O'Gorman AM, Deluca HF (1979) Reduced serum 1,25-(OH)2 vitamin D3 levels in prednisone-treated adolescents with systemic lupus erythematosus. Acta Paediatr Scand 68(1):109–111

    Article  PubMed  Google Scholar 

  43. Muller K, Kriegbaum NJ, Baslund B, Sorensen OH, Thymann M, Bentzen K (1995) Vitamin D3 metabolism in patients with rheumatic diseases: low serum levels of 25-hydroxyvitamin D3 in patients with systemic lupus erythematosus. Clin Rheumatol 14(4):397–400

    Article  PubMed  CAS  Google Scholar 

  44. Becker A, Fischer R, Schneider M (2001) Bone density and 25-OH vitamin D serum level in patients with systemic lupus erythematosus. Z Rheumatol 60(5):352–358

    Article  PubMed  CAS  Google Scholar 

  45. Kamen DL, Cooper GS, Bouali H, Shaftman SR, Hollis BW, Gilkeson GS (2006) Vitamin D deficiency in systemic lupus erythematosus. Autoimmun Rev 5(2):114–117

    Article  PubMed  CAS  Google Scholar 

  46. Thudi A, Yin S, Wandstrat AE, Li QZ, Olsen NJ (2008) Vitamin D levels and disease status in Texas patients with systemic lupus erythematosus. Am J Med Sci 335(2):99–104

    Article  PubMed  Google Scholar 

  47. Ruiz-Irastorza G, Egurbide MV, Olivares N, Martinez-Berriotxoa A, Aguirre C (2008) Vitamin D deficiency in systemic lupus erythematosus: prevalence, predictors and clinical consequences. Rheumatology (Oxford) 47(6):920–923

    Article  CAS  Google Scholar 

  48. Ruiz-Irastorza G, Gordo S, Olivares N, Egurbide MV, Aguirre C (2010) Changes in vitamin D levels in patients with systemic lupus erythematosus: effects on fatigue, disease activity, and damage. Arthritis Care Res (Hoboken) 62(8):1160–1165

    Article  CAS  Google Scholar 

  49. Wu PW, Rhew EY, Dyer AR, Dunlop DD, Langman CB, Price H et al (2009) 25-Hydroxyvitamin D and cardiovascular risk factors in women with systemic lupus erythematosus. Arthritis Rheum 61(10):1387–1395

    Article  PubMed  CAS  Google Scholar 

  50. Damanhouri LH, Vitamin D (2009) Deficiency in Saudi patients with systemic lupus erythematosus. Saudi Med J 30(10):1291–1295

    PubMed  Google Scholar 

  51. Toloza SM, Cole DE, Gladman DD, Ibanez D, Urowitz MB (2010) Vitamin D insufficiency in a large female SLE cohort. Lupus 19(1):13–19

    Article  PubMed  CAS  Google Scholar 

  52. Ben-Zvi I, Aranow C, Mackay M, Stanevsky A, Kamen DL, Marinescu LM et al (2010) The impact of vitamin D on dendritic cell function in patients with systemic lupus erythematosus. PLoS One 5(2):e9193

    Article  PubMed  Google Scholar 

  53. Kim HA, Sung JM, Jeon JY, Yoon JM, Suh CH (2010) Vitamin D may not be a good marker of disease activity in Korean patients with systemic lupus erythematosus. Rheumatol Int 31:1189–1194

    Article  PubMed  Google Scholar 

  54. Amital H, Szekanecz Z, Szucs G, Danko K, Nagy E, Csepany T et al (2010) Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: is it time to routinely supplement patients with SLE with vitamin D? Ann Rheum Dis 69(6):1155–1157

    Article  PubMed  CAS  Google Scholar 

  55. Zheng YJ, Chen S, Li ZQ, Yuan M, Ao W, Bao CD et al (2010) The relationship of vitamin D endocrine system and estrogen receptor expression with bone mineral density in initial systemic lupus erythematosus. Zhonghua Nei Ke Za Zhi 49(4):309–312

    PubMed  CAS  Google Scholar 

  56. Szodoray P, Tarr T, Bazso A, Poor G, Szegedi G, Kiss E (2010) The immunopathological role of vitamin D in patients with SLE: data from a single centre registry in Hungary. Scand J Rheumatol 40:122–126

    PubMed  Google Scholar 

  57. Huisman AM, White KP, Algra A, Harth M, Vieth R, Jacobs JW et al (2001) Vitamin D levels in women with systemic lupus erythematosus and fibromyalgia. J Rheumatol 28(11):2535–2539

    PubMed  CAS  Google Scholar 

  58. Wright TB, Shults J, Leonard MB, Zemel BS, Burnham JM (2009) Hypovitaminosis D is associated with greater body mass index and disease activity in pediatric systemic lupus erythematosus. J Pediatr 155(2):260–265

    Article  PubMed  CAS  Google Scholar 

  59. Borba VZ, Vieira JG, Kasamatsu T, Radominski SC, Sato EI, Lazaretti-Castro M (2009) Vitamin D deficiency in patients with active systemic lupus erythematosus. Osteoporos Int 20(3):427–433

    Article  PubMed  CAS  Google Scholar 

  60. Lora P, Scalco R, Furlanetto TW, Xavier RM (2008) Vitamin D status in patients with systemic lupus erythematosus from southern Brazil, vol 46(Supplement: IFCC WorldLab Fortaleza 2008. Clinical Chemistry and Laboratory Medicine, Walter de Gruyter, New York, p 7

    Google Scholar 

  61. Souto M, Coelho A, Guo C, Mendonca L, Argolo S, Papi J et al (2011) Vitamin D insufficiency in Brazilian patients with SLE: prevalence, associated factors, and relationship with activity. Lupus 20(10):1019–1026

    Article  PubMed  CAS  Google Scholar 

  62. Mok CC, Birmingham DJ, Leung HW, Hebert LA, Song H, Rovin BH (2011) Vitamin D levels in Chinese patients with systemic lupus erythematosus: relationship with disease activity, vascular risk factors and atherosclerosis. Rheumatology (Oxford) 51(4):644–652

    Article  Google Scholar 

  63. Carvalho JF, Blank M, Kiss E, Tarr T, Amital H, Shoenfeld Y (2007) Anti-vitamin D, vitamin D in SLE: preliminary results. Ann N Y Acad Sci 1109:550–557

    Article  PubMed  CAS  Google Scholar 

  64. Bogaczewicz J, Sysa-Jedrzejowska A, Arkuszewska C, Zabek J, Kontny E, Wozniacka A (2010) Prevalence of autoantibodies directed against 1,25(OH)2D3 in patients with systemic lupus erythematosus. Pol Merkur Lekarski 28(164):103–107

    PubMed  CAS  Google Scholar 

  65. Al-Janadi M, Al-Balla S, Al-Dalaan A, Raziuddin S (1993) Cytokine profile in systemic lupus erythematosus, rheumatoid arthritis, and other rheumatic diseases. J Clin Immunol 13(1):58–67

    Article  PubMed  CAS  Google Scholar 

  66. Evans RM (1988) The steroid and thyroid hormone receptor superfamily. Science 240(4854):889–895

    Article  PubMed  CAS  Google Scholar 

  67. Ozaki Y, Nomura S, Nagahama M, Yoshimura C, Kagawa H, Fukuhara S (2000) Vitamin-D receptor genotype and renal disorder in Japanese patients with systemic lupus erythematosus. Nephron 85(1):86–91

    Article  PubMed  CAS  Google Scholar 

  68. Huang CM, Wu MC, Wu JY, Tsai FJ (2002) Association of vitamin D receptor gene BsmI polymorphisms in Chinese patients with systemic lupus erythematosus. Lupus 11(1):31–34

    Article  PubMed  CAS  Google Scholar 

  69. Sakulpipatsin W, Verasertniyom O, Nantiruj K, Totemchokchyakarn K, Lertsrisatit P, Janwityanujit S (2006) Vitamin D receptor gene BsmI polymorphisms in Thai patients with systemic lupus erythematosus. Arthritis Res Ther 8(2):R48

    Article  PubMed  Google Scholar 

  70. Abbasi M, Rezaieyazdi Z, Afshari JT, Hatef M, Sahebari M, Saadati N (2010) Lack of association of vitamin D receptor gene BsmI polymorphisms in patients with systemic lupus erythematosus. Rheumatol Int 30(11):1537–1539

    Article  PubMed  CAS  Google Scholar 

  71. Huang CM, Wu MC, Wu JY, Tsai FJ (2002) No association of vitamin D receptor gene start codon fok 1 polymorphisms in Chinese patients with systemic lupus erythematosus. J Rheumatol 29(6):1211–1213

    PubMed  CAS  Google Scholar 

  72. Lee YH, Bae SC, Choi SJ, Ji JD, Song GG (2011) Associations between vitamin D receptor polymorphisms and susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis. Mol Biol Rep 38:3643–3651

    Article  PubMed  CAS  Google Scholar 

  73. Monticielo OA, Brenol JC, Chies JA, Longo MG, Rucatti GG, Scalco R et al (2012) The role of BsmI and FokI vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D in Brazilian patients with systemic lupus erythematosus. Lupus 21(1):43–52

    Article  PubMed  CAS  Google Scholar 

  74. Luo XY, Wu LJ, Yang MH, Liu NT, Liao T, Tang Z et al (2011) Relationship of vitamin D receptor gene Fok I polymorphism with systemic lupus erythematosus. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 27(8):901–905

    PubMed  CAS  Google Scholar 

  75. Luo XY, Yang MH, Wu FX, Wu LJ, Chen L, Tang Z et al (2011) Vitamin D receptor gene BsmI polymorphism B allele, but not BB genotype, is associated with systemic lupus erythematosus in a Han Chinese population. Lupus 21(1):53–59

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Fundo de Incentivo à Pesquisa e Eventos of the Hospital de Clínicas de Porto Alegre, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, and Conselho Nacional de Desenvolvimento Científico e Tecnológico.

Disclosures

None.

Author information

Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2350—Largo Eduardo Zaccaro Faraco, Sala 645, 6º andar, Porto Alegre, 90035-903, Rio Grande do Sul, Brazil

    Odirlei André Monticielo, Thaisa de Mattos Teixeira, João Carlos Tavares Brenol & Ricardo Machado Xavier

  2. Department of Genetics, Universidade Federal do Rio Grande do Sul, Avenida Bento Gonçalves, 9500—Agronomia, laboratório 212, prédio 43323, Porto Alegre, 91501-970, Rio Grande do Sul, Brazil

    José Artur Bogo Chies

Authors
  1. Odirlei André Monticielo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thaisa de Mattos Teixeira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. José Artur Bogo Chies
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. João Carlos Tavares Brenol
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ricardo Machado Xavier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Odirlei André Monticielo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Monticielo, O.A., Teixeira, T.d.M., Chies, J.A.B. et al. Vitamin D and polymorphisms of VDR gene in patients with systemic lupus erythematosus. Clin Rheumatol 31, 1411–1421 (2012). https://doi.org/10.1007/s10067-012-2021-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-012-2021-5

Keywords

Search

Navigation