Research Article| Volume 367, P148-151, August 15, 2016

Download started.


Predisposing role of vitamin D receptor (VDR) polymorphisms in the development of multiple sclerosis: A case-control study


      • The vitamin D receptor (VDR) plays a central role in vitamin D metabolism, both as a mediator of biological effects and also as the regulator of vitamin D metabolism.
      • Most effects of vitamin D are mediated by the binding of 1, 25(OH) 2D to the VDR.
      • VDR and its ligand have shown relative immunosuppressive and anti-inflammatory role.
      • Genome-wide association studies (GWAS) suggested more than 20 loci in MS susceptibility, including VDR gene.
      • The VDR polymorphisms affect its structure and function and it is believed that have a link with an increased risk of MS.


      Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) with a complex etiology. Given the Vitamin D receptor (VDR) gene, it is considered an outstanding risk component associated with MS. The aim of the present study has been to explore and emphasize the role of ApaI, BsmI, TaqI and FokI polymorphisms of VDR gene in susceptibility to MS in an Iranian case-control population including 160 patients and 150 healthy controls. All cases were clinically diagnosed with relapsing-remitting (RR) form, and the controls were age, gender, and race matched which were completely in agreement with the case group. PCR-R FLP was conducted for all the SNPs genotyping. The findings of the study showed a significant difference in allele frequency between the cases and controls for ApaI (p < 0.0002), BsmI (p < 0.0002) and TaqI (p < 0.0001), while no significant difference was observed for FokI (P > 0.0125). The results also showed that AA genotype polymorphism of ApaI and BsmI (OR = 4.6 and OR = 2.52, respectively), CC genotype of TaqI (OR = 2.41) and AC genotype of ApaI (OR = 1.79) are associated with the disease status. Nevertheless, the results revealed the protective role of TT genotype of TaqI (ORs < 1), CC genotype of Apal, and GG genotype of BsmI (ORs < 1). VDR polymorphisms seem to have a notable connection with MS pathogenesis, however, study of more big population and functional work on the gene structure and its function are recommended.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Compston A.
        • Coles A.
        Multiple sclerosis.
        Lancet (Lond. Engl.). Oct 25 2008; 372 (PubMed PMID: 18970977, Epub 2008/10/31. eng): 1502-1517
        • Heydarpour P.
        • Khoshkish S.
        • Abtahi S.
        • Moradi-Lakeh M.
        • Sahraian M.A.
        Multiple sclerosis epidemiology in Middle East and North Africa: a systematic review and meta-analysis.
        Neuroepidemiology. 2015; 44: 232-244
        • Sahraian M.A.
        • Khorramnia S.
        • Ebrahim M.M.
        • Moinfar Z.
        • Lotfi J.
        • Pakdaman H.
        Multiple sclerosis in Iran: a demographic study of 8,000 patients and changes over time.
        Eur. Neurol. 2010; 64: 331-336
        • Song G.G.
        • Choi S.J.
        • Ji J.D.
        • Lee Y.H.
        Genome-wide pathway analysis of a genome-wide association study on multiple sclerosis.
        Mol. Biol. Rep. 2013; 40: 2557-2564
        • Oksenberg J.R.
        • Baranzini S.E.
        • Sawcer S.
        • Hauser S.L.
        The genetics of multiple sclerosis: SNPs to pathways to pathogenesis.
        Nat. Rev. Genet. 2008; 9: 516-526
        • Beecham A.
        • Patsopoulos N.
        • Xifara D.
        • Davis M.
        • Kemppinen A.
        • Cotsapas C.
        • et al.
        International Multiple Sclerosis Genetics Consortium (IMSGC); Wellcome Trust Case Control Consortium 2 (WTCCC2); International IBD Genetics Consortium (IIBDGC).
        in: Analysis of Immune-Related Loci Identifies 48 New Susceptibility Variants for Multiple Sclerosis. Nat Genet. 45(11). 2013: 1353-1360
        • Consortium I.M.S.G.
        2 WTCCC. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.
        Nature. 2011; 476: 214-219
        • Consortium I.M.S.G.
        MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis.
        Brain. 2013; 136: 1778-1782
        • Hewer S.
        • Lucas R.
        • van der Mei I.
        • Taylor B.V.
        Vitamin D and multiple sclerosis.
        J. Clin. Neurosci. 2013; 20: 634-641
        • Soilu-Hänninen M.
        • Laaksonen M.
        • Laitinen I.
        • Erälinna J.
        • Lilius E.
        • Mononen I.
        A longitudinal study of serum 25-hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis.
        J. Neurol. Neurosurg. Psychiatry. 2008; 79: 152-157
        • Munger K.L.
        • Levin L.I.
        • Hollis B.W.
        • Howard N.S.
        • Ascherio A.
        Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis.
        J. Am. Med. Assoc. 2006; 296: 2832-2838
        • Lemire J.M.
        • Archer D.C.
        1, 25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis.
        J. Clin. Investig. 1991; 87: 1103
        • Adorini L.
        • Penna G.
        Control of autoimmune diseases by the vitamin D endocrine system.
        Nat. Clin. Pract. Rheumatol. 2008; 4: 404-412
        • Boonstra A.
        • Barrat F.J.
        • Crain C.
        • Heath V.L.
        • Savelkoul H.F.
        • O'Garra A.
        1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells.
        J. Immunol. Nov 1 2001; 167 (PubMed PMID: 11673504, Epub 2001/10/24. eng): 4974-4980
        • Narooie-Nejad M.
        • Moossavi M.
        • Torkamanzehi A.
        • Moghtaderi A.
        Positive association of vitamin D receptor gene variations with multiple sclerosis in South East Iranian population.
        BioMed Res. Int. 2015; 2015
        • Sioka C.
        • Papakonstantinou S.
        • Markoula S.
        • Gkartziou F.
        • Georgiou A.
        • Georgiou I.
        • et al.
        Vitamin D receptor gene polymorphisms in multiple sclerosis patients in Northwest Greece.
        J. Negat. Results Biomed. 2011; 10 (PubMed PMID: 21545713. Pubmed Central PMCID: PMC3097159. Epub 2011/05/07. eng): 3
        • Smolders J.
        • Peelen E.
        • Thewissen M.
        • Menheere P.
        • Tervaert J.W.C.
        • Hupperts R.
        • et al.
        The relevance of vitamin D receptor gene polymorphisms for vitamin D research in multiple sclerosis.
        Autoimmun. Rev. 2009; 8: 621-626
        • Moghtaderi A.
        • Tamadon G.
        • Haghighi F.
        25-hydroxyvitamin D3 concentration in serum and cerebrospinal fluid of patients with remitting-relapse multiple sclerosis.
        Prague Med. Rep. 2013; 114: 162-171
        • Mokry L.E.
        • Ross S.
        • Ahmad O.S.
        • Forgetta V.
        • Smith G.D.
        • Leong A.
        • et al.
        Vitamin D and risk of multiple sclerosis: a Mendelian randomization study.
        PLoS Med. 2015; 12e1001866
        • Landry C.S.
        • Ruppe M.D.
        • Grubbs E.G.
        Vitamin D receptors and parathyroid glands.
        Endocr. Pract. 2010; 17: 63-68
        • Kooloos W.M.
        • Wessels J.A.
        • van der Straaten T.
        • Huizinga T.W.
        • Guchelaar H.-J.
        Criteria for the selection of single nucleotide polymorphisms in pathway pharmacogenetics: TNF inhibitors as a case study.
        Drug Discov. Today. 2009; 14: 837-844
        • Al-Temaimi R.A.
        • Al-Enezi A.
        • Al-Serri A.
        • Al-Roughani R.
        • Al-Mulla F.
        The Association of Vitamin D Receptor Polymorphisms with multiple sclerosis in a case-control study from Kuwait.
        PLoS ONE. 2015; 10e0142265
        • Uitterlinden A.G.
        • Fang Y.
        • van Meurs J.B.
        • Pols H.A.
        • van Leeuwen J.P.
        Genetics and biology of vitamin D receptor polymorphisms.
        Gene. 2004; 338: 143-156
        • Whitfield G.K.
        • Remus L.S.
        • Jurutka P.W.
        • Zitzer H.
        • Oza A.K.
        • Dang H.T.
        • et al.
        Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene.
        Mol. Cell. Endocrinol. 2001; 177: 145-159
        • Gross C.
        • Krishnan A.V.
        • Malloy P.J.
        • Eccleshall T.R.
        • Zhao X.Y.
        • Feldman D.
        The vitamin D receptor gene start codon polymorphism: a functional analysis of FokI variants.
        J. Bone Miner. Res. 1998; 13: 1691-1699
        • Tajouri L.
        • Ovcaric M.
        • Curtain R.
        • Johnson M.P.
        • Griffiths L.R.
        • Csurhes P.
        • et al.
        Variation in the vitamin D receptor gene is associated with multiple sclerosis in an Australian population.
        J. Neurogenet. 2005; 19: 25-38
        • Tizaoui K.
        • Kaabachi W.
        • Hamzaoui A.
        • Hamzaoui K.
        Association between vitamin D receptor polymorphisms and multiple sclerosis: systematic review and meta-analysis of case–control studies.
        Cell. Mol. Immunol. 2015; 12: 243-252
        • Niino M.
        • Fukazawa T.
        • Yabe I.
        • Kikuchi S.
        • Sasaki H.
        • Tashiro K.
        Vitamin D receptor gene polymorphism in multiple sclerosis and the association with HLA class II alleles.
        J. Neurol. Sci. 2000; 177: 65-71
        • Simon K.C.
        • Munger K.L.
        • Yang X.
        • Ascherio A.
        Polymorphisms in vitamin D metabolism related genes and risk of multiple sclerosis.
        Mult. Scler. 2010; 16: 133-138
        • Narooie-Nejad M.
        • Moossavi M.
        • Torkamanzehi A.
        • Moghtaderi A.
        • Salimi S.
        Vitamin D receptor gene polymorphism and the risk of multiple sclerosis in South Eastern of Iran.
        J. Mol. Neurosci. 2015; 1-5
        • Shojapuor M.
        • Mosayebi G.
        • Ghasami K.
        • Ghazavi A.
        • Sadeghi A.
        Vitamin D receptor gene polymorphism in patients with multiple sclerosis in Mar kazi Province.
        Arak Med. Univ. J. 2012; 15: 34-39
        • Fukazawa T.
        • Yabe I.
        • Kikuchi S.
        • Sasaki H.
        • Hamada T.
        • Miyasaka K.
        • et al.
        Association of vitamin D receptor gene polymorphism with multiple sclerosis in Japanese.
        J. Neurol. Sci. 1999; 166: 47-52
        • Agliardi C.
        • Guerini F.R.
        • Saresella M.
        • Caputo D.
        • Leone M.A.
        • Zanzottera M.
        • et al.
        Vitamin D receptor (VDR) gene SNPs influence VDR expression and modulate protection from multiple sclerosis in HLA-DRB1* 15-positive individuals.
        Brain Behav. Immun. 2011; 25: 1460-1467
        • Smolders J.
        • Damoiseaux J.
        • Menheere P.
        • Tervaert J.W.C.
        • Hupperts R.
        Association study on two vitamin D receptor gene polymorphisms and vitamin D metabolites in multiple sclerosis.
        Ann. N. Y. Acad. Sci. 2009; 1173: 515-520
        • García-Martín E.
        • Agúndez J.
        • Martínez C.
        • Benito-León J.
        • Millán-Pascual J.
        • Calleja P.
        • et al.
        Vitamin D3 receptor (VDR) gene rs2228570 (Fok1) and rs731236 (Taq1) variants are not associated with the risk for multiple sclerosis: results of a new study and a meta-analysis.
        PLoS ONE. 2013; 8e65487
        • Partridge J.
        • Weatherby S.
        • Woolmore J.
        • Highland D.
        • Fryer A.
        • Mann C.
        • et al.
        Susceptibility and outcome in MS associations with polymorphisms in pigmentation-related genes.
        Neurology. 2004; 62: 2323-2325