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Vitamin D receptor (VDR) gene polymorphism and risk of rheumatoid arthritis (RA): systematic review and meta-analysis

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Abstract

Vitamin D is involved in immune system modulation as well as in calcium and bone homeostasis, hence plays a role in rheumatoid arthritis (RA) etiopathogenesis. A bulk of studies in different populations have assessed the association between the vitamin D receptor (VDR) gene polymorphisms and the risk of RA, reporting conflicting results. Therefore, we designed a meta-analysis to comprehensively evaluate the association of VDR gene polymorphisms and RA risk. All potential studies reporting the association between VDR gene polymorphisms and susceptibility to RA published till February 2020 were retrieved through systematic search of database, including Scopus and MEDLINE. Strength of pooled association was determined through calculating the pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analysis was performed by stratifying the studies by population type. This meta-analysis included 23 eligible studies (21 articles) overall. We noticed that FokI SNP had a significant protective association with susceptibility to RA in the overall analysis as well as in Europeans and Asians. TaqI SNP decreased the RA risk in Africans and Arabs, but not in the overall analysis. Likewise, BsmI SNP and RA risk in the overall population analysis was not significant. Interestingly, BsmI polymorphism increased RA risk in Africans. This meta-analysis offers a significant association between VDR gene polymorphism and susceptibility to RA in both overall and ethnic-specific analysis. However, different polymorphisms acted inversely in increasing or decreasing RA risk in different populations.

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References

  1. McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365(23):2205–2219

    CAS  PubMed  Google Scholar 

  2. Abbasi M, Mousavi MJ, Jamalzehi S, Alimohammadi R, Bezvan MH, Mohammadi H, Aslani S (2019) Strategies toward rheumatoid arthritis therapy; the old and the new. J Cell Physiol 234(7):10018–10031

    CAS  PubMed  Google Scholar 

  3. Mousavi MJ, Jamshidi A, Chopra A, Aslani S, Akhlaghi M, Mahmoudi M (2019) Implications of the noncoding RNAs in rheumatoid arthritis pathogenesis. J Cell Physiol 234(1):335–347

    CAS  Google Scholar 

  4. Sangha O (2000) Epidemiology of rheumatic diseases. Rheumatology 39(suppl_2):3–12

    PubMed  Google Scholar 

  5. Tobón GJ, Youinou P, Saraux A (2010) The environment, geo-epidemiology, and autoimmune disease: rheumatoid arthritis. Autoimmun Rev 9(5):A288–A292

    PubMed  Google Scholar 

  6. Conigliaro P, Triggianese P, de Martino E, Fonti GL, Chimenti MS, Sunzini F, Viola A, Canofari C, Perricone R (2019) Challenges in the treatment of rheumatoid arthritis. Autoimmun Rev 18:706–713

    PubMed  Google Scholar 

  7. Orozco G, Barton A (2010) Update on the genetic risk factors for rheumatoid arthritis. Expert Rev Clin Immunol 6(1):61–75

    PubMed  Google Scholar 

  8. Holoshitz J (2010) The rheumatoid arthritis HLA-DRB1 shared epitope. Curr Opin Rheumatol 22(3):293–298

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Karami J, Aslani S, Jamshidi A, Garshasbi M, Mahmoudi M (2019) Genetic implications in the pathogenesis of rheumatoid arthritis; an updated review. Gene 702:8–16

    CAS  PubMed  Google Scholar 

  10. Gonzalez-Escribano M et al (1999) CTLA4 polymorphisms in Spanish patients with rheumatoid arthritis. Tissue Antigens 53(3):296–300

    CAS  PubMed  Google Scholar 

  11. Lee YH, Rho YH, Choi SJ, Ji JD, Song GG (2007) PADI4 polymorphisms and rheumatoid arthritis susceptibility: a meta-analysis. Rheumatol Int 27(9):827–833

    CAS  PubMed  Google Scholar 

  12. Berkun Y, Levartovsky D, Rubinow A, Orbach H, Aamar S, Grenader T, Abou Atta I, Mevorach D, Friedman G, Ben-Yehuda A (2004) Methotrexate related adverse effects in patients with rheumatoid arthritis are associated with the A1298C polymorphism of the MTHFR gene. Ann Rheum Dis 63(10):1227–1231

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Razi B et al (2019) TIM family gene polymorphism and susceptibility to rheumatoid arthritis: systematic review and meta-analysis. PLoS One 14(2):e0211146

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee YH, Bae SC, Choi SJ, Ji JD, Song GG (2012) Associations between TNFAIP3 gene polymorphisms and rheumatoid arthritis: a meta-analysis. Inflamm Res 61(6):635–641

    CAS  PubMed  Google Scholar 

  15. Ebrahimiyan H, Mostafaei S, Aslani S, Jamshidi A, Mahmoudi M (2019) Studying the association between STAT4 gene polymorphism and susceptibility to rheumatoid arthritis disease: an updated meta-analysis. Iranian J Immunol 16(1):71–83

    Google Scholar 

  16. Mohammadi SA et al (2018) IL27 gene single nucleotide polymorphisms confer susceptibility to rheumatoid arthritis in Iranian population. Meta Gene 18:149–152

    Google Scholar 

  17. Kalueff A et al (2006) The vitamin D neuroendocrine system as a target for novel neurotropic drugs. CNS Neurol Disord Drug Targets 5(3):363–371

    CAS  PubMed  Google Scholar 

  18. Adorini L (2002) Immunomodulatory effects of vitamin D receptor ligands in autoimmune diseases. Int Immunopharmacol 2(7):1017–1028

    CAS  PubMed  Google Scholar 

  19. Ranganathan P (2009) Genetics of bone loss in rheumatoid arthritis—role of vitamin D receptor polymorphisms. Rheumatology 48(4):342–346

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sun J (2010) Vitamin D and mucosal immune function. Curr Opin Gastroenterol 26(6):591–595

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Tian Y, Wang C, Ye Z, Xiao X, Kijlstra A, Yang P (2012) Effect of 1, 25-dihydroxyvitamin D3 on Th17 and Th1 response in patients with Behcet's disease. Invest Ophthalmol Vis Sci 53(10):6434–6441

    CAS  PubMed  Google Scholar 

  22. Nagpal S, Na S, Rathnachalam R (2005) Noncalcemic actions of vitamin D receptor ligands. Endocr Rev 26(5):662–687

    CAS  PubMed  Google Scholar 

  23. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A (2006) Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. Jama 296(23):2832–2838

    CAS  PubMed  Google Scholar 

  24. Shoenfeld N, Amital H, Shoenfeld Y (2009) The effect of melanism and vitamin D synthesis on the incidence of autoimmune disease. Nat Clin Pract Rheumatol 5(2):99–105

    CAS  PubMed  Google Scholar 

  25. Uitterlinden AG et al (2004) Vitamin D receptor gene polymorphisms in relation to vitamin D related disease states. J Steroid Biochem Mol Biol 89:187–193

    PubMed  Google Scholar 

  26. Makoui, M.H., Vitamin D receptor gene polymorphisms and the risk of the type 1 diabetes: a meta-analysis based on 40 case–control studies. Department of Immunology, School of Public Health, Tehran University of …

  27. Imani D, Razi B, Motallebnezhad M, Rezaei R (2019) Association between vitamin D receptor (VDR) polymorphisms and the risk of multiple sclerosis (MS): an updated meta-analysis. BMC Neurol 19(1):339

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Makoui MH, Imani D, Motallebnezhad M, Azimi M, Razi B (2020) Vitamin D receptor gene polymorphism and susceptibility to asthma: meta-analysis based on 17 case–control studies. Ann Allergy Asthma Immunol 124(1):57–69

    CAS  PubMed  Google Scholar 

  29. Uitterlinden AG, Fang Y, van Meurs JBJ, Pols HAP, van Leeuwen JPTM (2004) Genetics and biology of vitamin D receptor polymorphisms. Gene 338(2):143–156

    CAS  PubMed  Google Scholar 

  30. Sundqvist E, Bäärnhielm M, Alfredsson L, Hillert J, Olsson T, Kockum I (2010) Confirmation of association between multiple sclerosis and CYP27B1. Eur J Hum Genet 18(12):1349–1352

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Maalej A, Petit-Teixeira E, Michou L, Rebai A, Cornelis F, Ayadi H (2005) Association study of VDR gene with rheumatoid arthritis in the French population. Genes Immun 6(8):707–711

    CAS  PubMed  Google Scholar 

  32. Mosaad YM, Hammad EM, Fawzy Z, Abdal Aal IA, Youssef HM, ElSaid TO, Monir R, el-Deek BS (2014) Vitamin D receptor gene polymorphism as possible risk factor in rheumatoid arthritis and rheumatoid related osteoporosis. Hum Immunol 75(5):452–461

    CAS  PubMed  Google Scholar 

  33. Ghelani AM, Samanta A, Jones AC, Mastana SS (2011) Association analysis of TNFR2, VDR, A2M, GSTT1, GSTM1, and ACE genes with rheumatoid arthritis in south Asians and Caucasians of East Midlands in the United Kingdom. Rheumatol Int 31(10):1355–1361

    CAS  PubMed  Google Scholar 

  34. Moher D, Liberati A, Tetzlaff J, Altman DG (2010) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg 8(5):336–341

    PubMed  Google Scholar 

  35. Stang A (2010) Critical evaluation of the Newcastle–Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603–605

    PubMed  Google Scholar 

  36. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    CAS  PubMed  Google Scholar 

  37. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22(4):719–748

    CAS  PubMed  Google Scholar 

  38. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    CAS  PubMed  Google Scholar 

  39. Egger M, Smith GD, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. Bmj 315(7109):629–634

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Garcia-Lozano J et al (2001) Association of vitamin D receptor genotypes with early onset rheumatoid arthritis. Eur J Immunogenet 28(1):89–93

    CAS  PubMed  Google Scholar 

  41. Lee C-K, Hong JS, Cho YS, Yoo B, Kim GS, Moon HB (2001) Lack of relationship between vitamin D receptor polymorphism. J Korean Med Sci 16:188–192

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Goertz B, Fassbender WJ, Williams JC, Marzeion AM, Bretzel RG, Stracke H, Berliner MN (2003) Vitamin D receptor genotypes are not associated with rheumatoid arthritis or biochemical parameters of bone turnover in German RA patients. Clin Exp Rheumatol 21(3):333–339

    CAS  PubMed  Google Scholar 

  43. Rass P, Pákozdi A, Lakatos P, Zilahi E, Sipka S, Szegedi G, Szekanecz Z (2006) Vitamin D receptor gene polymorphism in rheumatoid arthritis and associated osteoporosis. Rheumatol Int 26(11):964–971

    CAS  PubMed  Google Scholar 

  44. Hitchon CA et al (2012) Vitamin D receptor polymorphism rs2228570 (Fok1) is associated with rheumatoid arthritis in North American natives. J Rheumatol 39(9):1792–1797

    CAS  PubMed  Google Scholar 

  45. Hussien YM, Shehata A, Karam RA, Alzahrani SS, Magdy H, el-Shafey AM (2013) Polymorphism in vitamin D receptor and osteoprotegerin genes in Egyptian rheumatoid arthritis patients with and without osteoporosis. Mol Biol Rep 40(5):3675–3680

    CAS  PubMed  Google Scholar 

  46. Karray EF, Ben Dhifallah I, Ben Abdelghani K, Ben Ghorbel I, Khanfir M, Houman H, Hamzaoui K, Zakraoui L (2012) Associations of vitamin D receptor gene polymorphisms FokI and BsmI with susceptibility to rheumatoid arthritis and Behçet's disease in Tunisians. Joint Bone Spine 79(2):144–148

    CAS  PubMed  Google Scholar 

  47. Y, H., Associations of vitamin D receptor gene polymorphisms with RA in the Han population of human in China. Zhong Nan Da Xue Xue, 2013: p. 310–316

  48. Li C, W.Y., Yin H and Yin S, The association between vitamin D, vitamin D receptor polymorphism and rheumatoid arthritis. Chinese Journal of Rheumatology 2013(17): p. 164–168

  49. Shukla S et al (2014) Role of PTPN22 and VDR gene polymorphisms in susceptibility to rheumatoid arthritis: a study from Central India. Adv Genom Genet 4:79–85

    Google Scholar 

  50. Tizaoui K, Kaabachi W, Ouled Salah M, Ben Amor A, Hamzaoui A, Hamzaoui K (2014) Vitamin D receptor TaqI and ApaI polymorphisms: a comparative study in patients with Behçet’s disease and rheumatoid arthritis in Tunisian population. Cell Immunol 290(1):66–71

    CAS  PubMed  Google Scholar 

  51. John P, Bhatti A, Ain N, Iqbal T, Sadaf T, Malik JM (2017) Case–control study of vitamin D receptor gene polymorphism in Pakistani rheumatoid arthritis patients. Rev Bras Reumatol 57(6):633–636

    Google Scholar 

  52. Saad, M.N., et al., Genetic case-control study for eight polymorphisms associated with rheumatoid arthritis. PLoS One, 2015. 10(\)

  53. Di Spigna G et al (2016) Vitamin D receptor polymorphisms as tool for early screening of severe bone loss in women patients with rheumatoid arthritis. Eur Rev Med Pharmacol Sci 20(22):4664–4669

    PubMed  Google Scholar 

  54. Khoja SO, el-Miedany Y, Iyer AP, Bahlas SM, Balamash KS, Elshal MF (2018) Associations of vitamin D levels and vitamin D receptor genotypes with patient-reported outcome/disease activity in patients with rheumatoid arthritis. Clin Lab 64(1):51–58

    PubMed  Google Scholar 

  55. Mahmoud SAAH et al (2018) Vitamin D deficiency and RS731236 (taq1) vitamin D receptor gene polymorphism as possible risk factors for rheumatoid arthritis and osteoarthritis. Acta Med Austriaca 34:209

    Google Scholar 

  56. Mukhtar M, Sheikh N, Suqaina SK, Batool A, Fatima N, Mehmood R, Nazir S (2019) Vitamin D receptor gene polymorphism: an important predictor of arthritis development. Biomed Res Int 2019:1–8

    Google Scholar 

  57. Rodríguez-Carrio J et al (2019) Vitamin D receptor polymorphism and DHCR7 contribute to the abnormal interplay between vitamin D and lipid profile in rheumatoid arthritis. Sci Rep 9(1):1–11

    Google Scholar 

  58. 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(6):3643–3651

    CAS  PubMed  Google Scholar 

  59. Tizaoui K, Hamzaoui K (2015) Association between VDR polymorphisms and rheumatoid arthritis disease: systematic review and updated meta-analysis of case–control studies. Immunobiology 220(6):807–816

    CAS  PubMed  Google Scholar 

  60. Song G, Bae S-C, Lee Y (2016) Vitamin D receptor FokI, BsmI, and TaqI polymorphisms and susceptibility to rheumatoid arthritis. Z Rheumatol 75(3):322–329

    CAS  PubMed  Google Scholar 

  61. Vinh Quốc Lương K, Nguyễn LTH (2012) The role of vitamin D in asthma. Pulm Pharmacol Ther 25(2):137–143

    Google Scholar 

  62. van Etten E, Verlinden L, Giulietti A, Ramos-Lopez E, Branisteanu DD, Ferreira GB, Overbergh L, Verstuyf A, Bouillon R, Roep BO, Badenhoop K, Mathieu C (2007) The vitamin D receptor gene FokI polymorphism: functional impact on the immune system. Eur J Immunol 37(2):395–405

    PubMed  Google Scholar 

  63. Lemos MC, Fagulha A, Coutinho E, Gomes L, Bastos M, Barros L, Carrilho F, Geraldes E, Regateiro FJ, Carvalheiro M (2008) Lack of association of vitamin D receptor gene polymorphisms with susceptibility to type 1 diabetes mellitus in the Portuguese population. Hum Immunol 69(2):134–138

    CAS  PubMed  Google Scholar 

  64. Vanessa O et al (2013) Vitamin D receptor gene expression and function in a South African population: ethnicity, vitamin D and FokI. PLoS One 8(6):e67663

    Google Scholar 

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Acknowledgments

We thank Dr. Bahman Razi for comments that greatly improved the manuscript.

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Authors and Affiliations

  1. Department of Clinical Biochemistry, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

    Zahra Bagheri-Hosseinabadi

  2. Molecular Medicine Research Center,Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

    Zahra Bagheri-Hosseinabadi & Mitra Abbasifard

  3. Department of Immunology, School of Public Health, Tehran University of Medical Sciences (TUMS), Tehran, Iran

    Danyal Imani

  4. Department of Biochemistry and Molecular Biology, School of Medicine, LSUHSC, New Orleans, LA, USA

    Hassan Yousefi

  5. Department of internal Medicine, Ali-Ibn Abi-Talib hospital, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

    Mitra Abbasifard

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  1. Zahra Bagheri-Hosseinabadi
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  2. Danyal Imani
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Contributions

Z.B. generated the idea. D.I. analyzed and interpreted the data. Z.B. and H.Y. prepared the original draft. Z.B., H.Y., and M.A. critically revised the paper. M.A. supervised the project. All authors read and approved the final manuscript.

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Correspondence to Mitra Abbasifard.

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Bagheri-Hosseinabadi, Z., Imani, D., Yousefi, H. et al. Vitamin D receptor (VDR) gene polymorphism and risk of rheumatoid arthritis (RA): systematic review and meta-analysis. Clin Rheumatol 39, 3555–3569 (2020). https://doi.org/10.1007/s10067-020-05143-y

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