Abstract
Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS), resulting from the interaction among genetic, epigenetic, and environmental factors. Vitamin D is a secosteroid, and its circulating levels are influenced by environment and genetics. In the last decades, research data on the association between MS and vitamin D status led to hypothesize a possible role for hypovitaminosis D as a risk factor for MS. Some gene variants encoding proteins involved in vitamin D metabolism, transport, and function, which are responsible for vitamin D status alterations, have been related to MS susceptibility. This review explores the current literature on the influence of vitamin D-related genes in MS susceptibility, reporting all single-nucleotide polymorphisms (SNPs) investigated to date in 12 vitamin D pathway genes. Among all, the gene codifying vitamin D receptor (VDR) is the most studied. The association between VDR SNPs and MS risk has been reported by many Authors, with a few studies producing opposite results. Other vitamin D-related genes (including DHCR7/NADSYN1, CYP2R1, CYP27A1, CYP3A4, CYP27B1, CYP24A1, Megalin-DAB2-Cubilin, FGF-23, and Klotho) have been less investigated and achieved more conflicting evidence. Taken together, findings from the studies reviewed cannot clarify whether and to what extent vitamin D-related gene variants can influence MS risk.
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Abdollahzadeh R, Fard MS, Rahmani F, Moloudi K, Kalani BS, Azarnezhad A (2016) Predisposing role of vitamin D receptor (VDR) polymorphisms in the development of multiple sclerosis: A case-control study. J Neurol Sci 367:148–51. https://doi.org/10.1016/j.jns.2016.05.053
Abdollahzadeh R, Moradi Pordanjani P, Rahmani F, Mashayekhi F, Azarnezhad A, Mansoori Y (2018) Association of VDR gene polymorphisms with risk of relapsing-remitting multiple sclerosis in an Iranian Kurdish population. Int J Neurosci 128(6):505–511. https://doi.org/10.1080/00207454.2017.1398158
Acheson ED, Bachrach CA, Wright FM (1960) Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables. Acta Psychiatr Scand Suppl 5(147):132–47
Agliardi C, Guerini FR, Saresella M, Caputo D, Leone MA, Zanzottera M, Bolognesi E, Marventano I, Barizzone N, Fasano ME, Al-Daghri N, Clerici M (2011) Vitamin D receptor (VDR) gene SNPs influence VDR expression and modulate protection from multiple sclerosis in HLA-DRB1*15-positive individuals. Brain Behav Immun 25(7):1460–7. https://doi.org/10.1016/j.bbi.2011.05.015
Agliardi C, Guerini FR, Zanzottera M, Bolognesi E, Costa AS, Clerici M (2017) Vitamin D-binding protein gene polymorphisms are not associated with MS risk in an Italian cohort. J Neuroimmunol 305:92–95. https://doi.org/10.1016/j.jneuroim.2017.02.009
Agnello L, Bellia C, Di Gangi M et al (2016) Utility of serum procalcitonin and C-reactive protein in severity assessment of community-acquired pneumonia in children. Clin Biochem 49(1–2):47–50. https://doi.org/10.1016/j.clinbiochem.2015.09.008
Agnello L, Bivona G, Lo Sasso B et al (2017) Galectin-3 in acute coronary syndrome. Clin Biochem 50(13–14):797–803. https://doi.org/10.1016/j.clinbiochem.2017.04.018
Agnello L, Bivona G, Novo G et al (2017) Heart-type fatty acid binding protein is a sensitive biomarker for early AMI detection in troponin negative patients: a pilot study. Scand J Clin Lab Invest 77(6):428–432. https://doi.org/10.1080/00365513.2017.1335880
Agnello L, Scazzone C, Lo Sasso B, Bellia C, Bivona G, Realmuto S, Brighina F, Schillaci R, Ragonese P, Salemi G, Ciaccio M (2017) VDBP, CYP27B1, and 25-Hydroxyvitamin D Gene Polymorphism Analyses in a Group of Sicilian Multiple Sclerosis Patients. Biochem Genet 55(2):183–192. https://doi.org/10.1007/s10528-016-9783-4
Agnello L, Scazzone C, Lo Sasso B, Ragonese P, Milano S, Salemi G, Ciaccio M (2018) CYP27A1, CYP24A1, and RXR-α polymorphisms, Vitamin D, and multiple sclerosis: a pilot study. J Mol Neurosci. 66(1):77–84. https://doi.org/10.1007/s12031-018-1152-9
Agnello L, Scazzone C, Ragonese P, Salemi G, Lo Sasso B, Schillaci R, Musso G, Bellia C, Ciaccio M (2016) Vitamin D receptor polymorphisms and 25-hydroxyvitamin D in a group of Sicilian multiple sclerosis patients. Neurol Sci 37(2):261–7. https://doi.org/10.1007/s10072-015-2401-0
Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, Gallicchio L, Jacobs EJ, Ascherio A, Helzlsouer K et al (2010) Genome-wide association study of circulating vitamin D levels. Hum Mol Genet 19(13):2739–45. https://doi.org/10.1093/hmg/ddq155
Al-Temaimi RA, Al-Enezi A, Al-Serri A, Alroughani R, Al-Mulla F (2015) The association of Vitamin D receptor polymorphisms with multiple sclerosis in a case-control study from Kuwait. PLoS One 10(11):e0142265. https://doi.org/10.1371/journal.pone.0142265
Alloza I, Otaegui D, de Lapuente AL, Antigüedad A, Varadé J, Núñez C, Arroyo R, Urcelay E, Fernandez O, Leyva L, Fedetz M, Izquierdo G, Lucas M, Oliver-Martos B, Alcina A, Saiz A, Blanco Y, Comabella M, Montalban X, Olascoaga J, Matesanz F, Vandenbroeck K (2012) ANKRD55 and DHCR7 are novel multiple sclerosis risk loci. Genes Immun 13(3):253–7. https://doi.org/10.1038/gene.2011.81
Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene) (2009) Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat Genet 41(7):824–8. https://doi.org/10.1038/ng.396
Ban M, Caillier S, Mero IL, Myhr KM, Celius EG, Aarseth J, Torkildsen Ø, Harbo HF, Oksenberg J, Hauser SL, Sawcer S, Compston A (2013) No evidence of association between mutant alleles of the CYP27B1 gene and multiple sclerosis. Ann Neurol 73(3):430–2. https://doi.org/10.1002/ana.23833
Baranzini SE, Oksenberg JR (2017) The genetics of multiple sclerosis: from 0 to 200 in 50 years. Trends Genet 33(12):960–970. https://doi.org/10.1016/j.tig.2017.09.004
Becker KG (2004) The common variants/multiple disease hypothesis of common complex genetic disorders. Med Hypotheses 62(2):309–17
Bellia C, Bivona G, Scazzone C et al (2007) Association between homocysteinemia and metabolic syndrome in patients with cardiovascular disease. Ther Clin Risk Manag 3(6):999–1001
Bellia C, Zaninotto M, Cosma C, Agnello L, Lo Sasso B, Bivona G, Plebani M, Ciaccio M (2017) Definition of the upper reference limit of glycated albumin in blood donors from Italy. Clin Chem Lab Med 56(1):120–125. https://doi.org/10.1515/cclm-2017-0179
Ben-Selma W, Ben-Fredj N, Chebel S, Frih-Ayed M, Aouni M, Boukadida J (2015) Age- and gender-specific effects on VDR gene polymorphisms and risk of the development of multiple sclerosis in Tunisians: a preliminary study. Int J Immunogenet 42(3):174–81. https://doi.org/10.1111/iji.12197
Bermúdez-Morales VH, Fierros G, Lopez RL, Martínez-Nava G, Flores-Aldana M, Flores-Rivera J, Hernández-Girón C (2017) Vitamin D receptor gene polymorphisms are associated with multiple sclerosis in Mexican adults. J Neuroimmunol 306:20–24. https://doi.org/10.1016/j.jneuroim.2017.01.009
Berridge MJ (2015) Vitamin D cell signalling in health and disease. Biochem Biophys Res Commun 460:53–71
Bettencourt A, Boleixa D, Guimarães AL, Leal B, Carvalho C, Brás S, Samões R, Santos E, Costa PP, Silva B, da Silva AM (2017) The vitamin D receptor gene FokI polymorphism and multiple sclerosis in a Northern Portuguese population. J Neuroimmunol 309:34–37. https://doi.org/10.1016/j.jneuroim.2017.05.005
Bezzini D, Battaglia MA (2017) Multiple sclerosis epidemiology in Europe. Adv Exp Med Biol 958:141–159. https://doi.org/10.1007/978-3-319-47861-6_9
Bikle DD (2009) Extra renal synthesis of 1,25-dihydroxyvitamin D and its health implications. Clinic Rev Bone Miner Metab 7:114–125
Bikle DD (2014) Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol 21(3):319–29. https://doi.org/10.1016/j.chembiol.2013.12.016
Bivona G, Agnello L, Ciaccio M (2018) The immunological implication of the new vitamin D metabolism. Cent Eur J Immunol 43(3):331–334. https://doi.org/10.5114/ceji.2018.80053
Bivona G, Agnello L, Lo Sasso B, Scazzone C, Butera D, Gambino CM, Iacolino G, Bellia C, Ciaccio M (2019) Vitamin D in malaria: more hypotheses than clues. Heliyon 5(2):e01183. https://doi.org/10.1016/j.heliyon.2019.e01183
Bivona G, Agnello L, Pivetti A, Milano S, Scazzone C, Sasso BL, Ciaccio M (2016) Association between hypovitaminosis D and systemic sclerosis: true or fake? Clin Chim Acta 458:115–9. https://doi.org/10.1016/j.cca.2016.04.026
Bivona G, Bellia C, Lo Sasso B, Agnello L, Scazzone C, Novo G, Ciaccio M (2016) Short-term changes in Gal 3 circulating levels after acute myocardial infarction. Arch Med Res 47(7):521–525. https://doi.org/10.1016/j.arcmed.2016.12.009
Bivona G, Lo Sasso B, Iacolino G, Gambino CM, Scazzone C, Agnello L, Ciaccio M (2019) Standardized measurement of circulating vitamin D [25(OH)D] and its putative role as a serum biomarker in Alzheimer’s disease and Parkinson’s disease. Clin Chim Acta 497:82–87. https://doi.org/10.1016/j.cca.2019.07.022
Brance ML, Miljevic JN, Tizziani R et al (2018) Serum 25-hydroxyvitamin D levels in hospitalized adults with community-acquired pneumonia. Clin Respir J 12(7):2220–2227. https://doi.org/10.1111/crj.12792
Caruso A, Bellia C, Pivetti A, Agnello L, Bazza F, Scazzone C, Bivona G, Lo Sasso B, Ciaccio M (2014) Effects of EPHX1 and CYP3A4 polymorphisms on carbamazepine metabolism in epileptic patients. Pharmgenomics Pers Med 7:117–20. https://doi.org/10.2147/PGPM.S55548
Chichiarelli S, Gaucci E, Ferraro A, Grillo C, Altieri F, Cocchiola R, Arcangeli V, Turano C, Eufemi M (2010) Role of ERp57 in the signaling and transcriptional activity of STAT3 in a melanoma cell line. Arch Biochem Biophys 494(2):178–83
Chiuso-Minicucci F, Ishikawa LL, Mimura LA, Fraga-Silva TF, França TG, Zorzella-Pezavento SF, Marques C, Ikoma MR, Sartori A (2015) Treatment with vitamin D/MOG association suppresses experimental autoimmune encephalomyelitis. PLoS One 10(5):e0125836. https://doi.org/10.1371/journal.pone.0125836
Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G (2016) Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev 96(1):365–408. https://doi.org/10.1152/physrev.00014.2015
Ciaccio M, Bivona G, Di Sciacca R et al (2008) Changes in serum fetuin-A and inflammatory markers levels in end-stage renal disease (ESRD): effect of a single session haemodialysis. Clin Chem Lab Med 46(2):212–4
Ciaccio M, Fugardi G, Titone L, Romano A, Giordano S, Bivona G, Scarlata F, Vocca L, Di Gangi M (2004) Procalcitonin levels in plasma in oncohaematologic patients with and without bacterial infections. Clinica Chimica Acta 340(1–2):149–152
Cierny D, Michalik J, Škereňová M, Kantorová E, Sivák Š, Javor J, Kurča E, Dobrota D, Lehotský J (2016) ApaI, BsmI and TaqI VDR gene polymorphisms in association with multiple sclerosis in Slovaks. Neurol Res 38(8):678–84. https://doi.org/10.1080/01616412.2016.1200287
Cleve H, Constans J (1988) The mutants of the vitamin-D-binding protein: more than 120 variants of the GC/DBP system. Vox Sang 54(4):215–25
Cox MB, Ban M, Bowden NA, Baker A, Scott RJ, Lechner-Scott J (2012) Potential association of vitamin D receptor polymorphism Taq1 with multiple sclerosis. Mult Scler 18(1):16–22. https://doi.org/10.1177/1352458511415562
Dastani Z, Li R, Richards B (2013) Genetic regulation of vitamin D levels. Calcif Tissue 92(2):106–17. https://doi.org/10.1007/s00223-012-9660-z
Dickinson JL, Perera DI, van der Mei AF, Ponsonby AL, Polanowski AM, Thomson RJ, Taylor BV, McKay JD, Stankovich J, Dwyer T (2009) Past environmental sun exposure and risk of multiple sclerosis: a role for the Cdx-2 Vitamin D receptor variant in this interaction. Mult Scler 15(5):563–70. https://doi.org/10.1177/1352458509102459
Disanto G, Sandve GK, Berlanga-Taylor AJ, Ragnedda G, Morahan JM, Watson CT, Giovannoni G, Ebers GC, Ramagopalan SV (2012) Vitamin D receptor binding, chromatin states and association with multiple sclerosis. Hum Mol Genet 21(16):3575–86. https://doi.org/10.1093/hmg/dds189
Fletcher JM, Lalor SJ, Sweeney CM, Tubridy N, Mills KH (2010) T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol 162(1):1–11. https://doi.org/10.1111/j.1365-2249.2010.04143.x
Fukazawa T, Yabe I, Kikuchi S, Sasaki H, Hamada T, Miyasaka K, Tashiro K (1999) Association of vitamin D receptor gene polymorphism with multiple sclerosis in Japanese. J Neurol Sci 166(1):47–52
Gao Q, Fan Y, Mu LY et al (2015) S100B and ADMA in cerebral small vessel disease and cognitive dysfunction. J Neurol Sci 354(1–2):27–32. https://doi.org/10.1016/j.jns.2015.04.031
García-Martín E, Agúndez JA, Martínez C, Benito-León J, Millán-Pascual J, Calleja P, Díaz-Sánchez M, Pisa D, Turpín-Fenoll L, Alonso-Navarro H, Ayuso-Peralta L, Torrecillas D, Plaza-Nieto JF, Jiménez-Jiménez FJ (2013) 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 8(6):e65487. https://doi.org/10.1371/journal.pone.0065487
Gauzzi MC (2018) Vitamin D-binding protein and multiple sclerosis: Evidence, controversies, and needs. Mult Scler 24(12):1526–1535. https://doi.org/10.1177/1352458518792433
Gianfrancesco MA, Stridh P, Rhead B, Shao X, Xu E, Graves JS, Chitnis T, Waldman A, Lotze T, Schreiner T, Belman A, Greenberg B, Weinstock-Guttman B, Aaen G, Tillema JM, Hart J, Caillier S, Ness J, Harris Y, Rubin J, Candee M, Krupp L, Gorman M, Benson L, Rodriguez M, Mar S, Kahn I, Rose J, Roalstad S, Casper TC, Shen L, Quach H, Quach D, Hillert J, Bäärnhielm M, Hedstrom A, Olsson T, Kockum I, Alfredsson L, Metayer C, Schaefer C, Barcellos LF, Waubant E (2017) Network of pediatric multiple sclerosis centers. Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS. Neurology. 88(17):1623–1629. https://doi.org/10.1212/WNL.0000000000003849
Giulia B, Luisa A, Concetta S et al (2015) Procalcitonin and community-acquired pneumonia (CAP) in children. Clin Chim Acta 451(Pt B):215–8. https://doi.org/10.1016/j.cca.2015.09.031
Glade MJ (2013) Vitamin D: health panacea or false prophet? Nutrition 29(1):37–41. https://doi.org/10.1016/j.nut.2012.05.010
Golden LC, Voskuhl R (2017) The importance of studying sex differences in disease: The example of multiple sclerosis. J Neurosci Res 95(1–2):633–643. https://doi.org/10.1002/jnr.23955
Goudarzvand M, Javan M, Mirnajafi-Zadeh J, Mozafari S, Tiraihi T (2010) Vitamins E and D3 attenuate demyelination and potentiate remyelination processes of hippocampal formation of rats following local injection of ethidium bromide. Cell Mol Neurobiol 30(2):289–99. https://doi.org/10.1007/s10571-009-9451-x
Graves JS, Barcellos LF, Krupp L, Belman A, Shao X, Quach H et al (2019) Vitamin D genes influence MS relapses in children. Mult Scler 13:1352458519845842. https://doi.org/10.1177/1352458519845842
Groves NJ, McGrath JJ, Burne TH (2014) Vitamin D as a neurosteroid affecting the developing and adult brain. Annu Rev Nutr 34:117–41. https://doi.org/10.1146/annurev-nutr-071813-105557
Guo LH, Alexopoulos P, Perneczky R (2013) Heart-type fatty acid binding protein and vascular endothelial growth factor: cerebrospinal fluid biomarker candidates for Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 263(7):553–60. https://doi.org/10.1007/s00406-013-0405-4
Herrmann M, Farrell CL, Pusceddu I, Fabregat-Cabello N, Cavalier E (2017) Assessment of vitamin D status - a changing landscape. Clin Chem Lab Med 55(1):3–26. https://doi.org/10.1515/cclm-2016-0264
Hettinghouse A, Liu R, Liu CJ (2018) Multifunctional molecule ERp57: From cancer to neurodegenerative diseases. Pharmacol Ther 181:34–48. https://doi.org/10.1016/j.pharmthera.2017.07.011
Hu Q, Teng W, Li J, Hao F et al (2016) Homocysteine and Alzheimer’s disease: evidence for a causal link from mendelian randomization. J Alzheimers Dis 52(2):747–56. https://doi.org/10.3233/JAD-150977
Huhtakangas JA, Olivera CJ, Bishop JE, Zanello LP, Norman AW (2004) The vitamin D receptor is present in caveolae-enriched plasma membranes and binds 1 alpha, 25(OH)2-vitamin D3 in vivo and in vitro. Mol Endocrinol 18(11):2660–71
Hunter SF (2016) Overview and diagnosis of multiple sclerosis. Am J Manag Care 22(6 Suppl):s141-50
Jeon SM, Shin EA (2018) Exploring vitamin D metabolism and function in cancer. Exp Mol Med 50(4):20. https://doi.org/10.1038/s12276-018-0038-9
Jolliffe DA, Walton RT, Griffiths CJ, Martineau AR (2016) Single nucleotide polymorphisms in the vitamin D pathway associating with circulating concentrations of vitamin D metabolites and non-skeletal health outcomes: Review of genetic association studies. J Steroid Biochem Mol Biol 164:18–29. https://doi.org/10.1016/j.jsbmb.2015.12.007
Kamisli O, Acar C, Sozen M, Tecellioglu M, Yücel FE, Vaizoglu D, Özcan C (2018) The association between vitamin D receptor polymorphisms and multiple sclerosis in a Turkish population. Mult Scler Relat Disord 20:78–81. https://doi.org/10.1016/j.msard.2018.01.002
Kim CJ, Kaplan LE, Perwad F, Huang N, Sharma A, Choi Y, Miller WL, Portale AA (2007) Vitamin D 1alpha-hydroxylase gene mutations in patients with 1alpha-hydroxylase deficiency. J Clin Endocrinol Metab 92(8):3177–82
Kosakai A, Ito D, Nihei Y, Yamashita S, Okada Y, Takahashi K, Suzuki N (2011) Degeneration of mesencephalic dopaminergic neurons in klotho mouse related to vitamin D exposure. Brain Res 1382:109–17
Kotter MR, Li WW, Zhao C, Franklin RJ (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 26(1):328–32
Křenek P, Benešová Y, Bienertová-Vašků J, Vašků A (2018) The impact of five VDR polymorphisms on multiple sclerosis risk and progression: a case-control and genotype-phenotype study. J Mol Neurosci 64(4):559–566. https://doi.org/10.1007/s12031-018-1034-1
Kuusisto H, Kaprio J, Kinnunen E, Luukkaala T, Koskenvuo M, Elovaara I (2008) Concordance and heritability of multiple sclerosis in Finland: study on a nationwide series of twins. Eur J Neurol 15(10):1106–10. https://doi.org/10.1111/j.1468-1331.2008.02262.x
Lambrinoudaki I, Patikas E, Kaparos G, Armeni E, Rizos D, Thoda P, Alexandrou A, Antoniou A, Tsivgoulis G, Gatzonis S, Panoulis C, Triantafyllou N (2013) Vitamin D receptor Bsm1 polymorphism, calcium metabolism and bone mineral density in patients with multiple sclerosis: a pilot study. Neurol Sci 34(8):1433–9. https://doi.org/10.1007/s10072-012-1259-7
Langer-Gould A, Lucas RM, Xiang AH, Wu J, Chen LH, Gonzales E, Haraszti S, Smith JB, Quach H, Barcellos LF (2018) Vitamin D-Binding Protein Polymorphisms, 25-Hydroxyvitamin D, Sunshine and Multiple Sclerosis. Nutrients 10(2):184. https://doi.org/10.3390/nu10020184
Laursen JH, Søndergaard HB, Albrechtsen A, Frikke-Schmidt R, Koch-Henriksen N, Soelberg Sørensen P, Sellebjerg F, Oturai A (2015) Genetic and environmental determinants of 25-hydroxyvitamin D levels in multiple sclerosis. Mult Scler 21(11):1414–22. https://doi.org/10.1177/1352458514563590
Legroux L, Arbour N (2015) Multiple sclerosis and T lymphocytes: an entangled story. J Neuroimmune Pharmacol 10(4):528–46. https://doi.org/10.1007/s11481-015-9614-0
Lemire JM, Archer DC (1991) 1,25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. J Clin Invest 87(3):1103–1107. https://doi.org/10.1172/JCI115072
Lin R, Taylor BV, Simpson S Jr, Charlesworth J, Ponsonby AL, Pittas F, Dwyer T, van der Mei I (2014) Association between multiple sclerosis risk-associated SNPs and relapse and disability–a prospective cohort study. Mult Scler 20(3):313–21. https://doi.org/10.1177/1352458513496882
Lindblom B, Wetterling G, Link H (1988) Distribution of group-specific component subtypes in multiple sclerosis. Acta Neurol Scand 78(5):443–4
Littlejohns TJ, Henley WE, Lang IA et al (2014) Vitamin D and the risk of dementia and Alzheimer disease. Neurology 83(10):920–8. https://doi.org/10.1212/WNL.0000000000000755
Lu M, Taylor BV, Körner H (2018) Genomic effects of the vitamin D receptor: potentially the link between vitamin D, immune cells, and multiple sclerosis. Front Immunol 9:477. https://doi.org/10.3389/fimmu.2018.00477
Mak A (2018) The impact of vitamin D on the immunopathophisiology, disease activity, and extra-muskuloskeletal manifestations of systemic erithematosus lupus. J Mol Sci 19(8):E2355
Mamutse G, Woolmore J, Pye E, Partridge J, Boggild M, Young C, Fryer A, Hoban PR, Rukin N, Alldersea J, Strange RC, Hawkins CP (2008) Vitamin D receptor gene polymorphism is associated with reduced disability in multiple sclerosis. Mult Scler 14(9):1280–3. https://doi.org/10.1177/1352458508094643
Manousaki D, Dudding T, Haworth S, Hsu YH, Liu CT, Medina-Gómez C, Voortman T, van der Velde N, Melhus H, Robinson-Cohen C, Cousminer DL, Nethander M et al (2017) Low-frequency synonymous coding variation in CYP2R1 has large effects on vitamin D levels and risk of multiple sclerosis. Am J Hum Genet 101(2):227–238. https://doi.org/10.1016/j.ajhg.2017.06.014
Martin A, David V, Quarles LD (2012) Regulation and function of the FGF23/klotho endocrine pathways. Physiol Rev 92(1):131–55. https://doi.org/10.1152/physrev.00002.2011
Matías-Guíu J, Oreja-Guevara C, Matias-Guiu JA, Gomez-Pinedo U (2018) Vitamin D and remyelination in multiple sclerosis. Neurologia 33(3):177–186. https://doi.org/10.1016/j.nrl.2016.05.001
Mimura LA, Chiuso-Minicucci F, Fraga-Silva TF, Zorzella-Pezavento SF, França TG, Ishikawa LL, Penitenti M, Ikoma MR, Sartori A (2016) Association of myelin peptide with vitamin D prevents autoimmune encephalomyelitis development. Neuroscience 317:130–40. https://doi.org/10.1016/j.neuroscience.2015.12.053
Mokry LE, Ross S, Ahmad OS, Forgetta V, Smith GD, Goltzman D, Leong A, Greenwood CM, Thanassoulis G, Richards JB (2015) Vitamin D and risk of multiple sclerosis: a mendelian randomization study. PLoS Med 12(8):e1001866. https://doi.org/10.1371/journal.pmed.1001866
Mowry EM, Krupp LB, Milazzo M, Chabas D, Strober JB, Belman AL, McDonald JC, Oksenberg JR, Bacchetti P, Waubant E (2010) Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol 67(5):618–24. https://doi.org/10.1002/ana.21972
Munger KL, Hongell K, Åivo J, Soilu-Hänninen M, Surcel HM, Ascherio A (2017) 25-Hydroxyvitamin D deficiency and risk of MS among women in the Finnish Maternity Cohort. Neurology 89(15):1578–1583. https://doi.org/10.1212/WNL.0000000000004489
Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A (2006) Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296(23):2832–8
Nagai J, Christensen EI, Morris SM, Willnow TE, Cooper JA, Nielsen R (2005) Mutually dependent localization of megalin and Dab2 in the renal proximal tubule. Am J Physiol Renal Physiol 289(3):F569-76
Narooie-Nejad M, Moossavi M, Torkamanzehi A, Moghtaderi A, Salimi S (2015) Vitamin D receptor gene polymorphism and the risk of multiple sclerosis in South Eastern of Iran. J Mol Neurosci 56(3):572–6. https://doi.org/10.1007/s12031-015-0513-x
Narooie-Nejad M, Moossavi M, Torkamanzehi A, Moghtaderi A (2015) Positive association of vitamin D receptor gene variations with multiple sclerosis in South East Iranian population. Biomed Res Int 2015:427519. https://doi.org/10.1155/2015/427519
Nielsen NM, Munger KL, Koch-Henriksen N, Hougaard DM, Magyari M, Jørgensen KT, Lundqvist M, Simonsen J, Jess T, Cohen A, Stenager E, Ascherio A (2017) Neonatal vitamin D status and risk of multiple sclerosis: A population-based case-control study. Neurology 88(1):44–51. https://doi.org/10.1212/WNL.0000000000003454
Nieves J, Cosman F, Herbert J, Shen V, Lindsay R (1994) High prevalence of vitamin D deficiency and reduced bone mass in multiple sclerosis. Neurology 44:1687–1692
Niino M, Fukazawa T, Yabe I, Kikuchi S, Sasaki H, Tashiro K (2000) Vitamin D receptor gene polymorphism in multiple sclerosis and the association with HLA class II alleles. J Neurol Sci 177(1):65–71
Niino M, Kikuchi S, Fukazawa T, Yabe I, Tashiro K (2002) No association of vitamin D-binding protein gene polymorphisms in Japanese patients with MS. J Neuroimmunol 127(1–2):177–9
Norman AW (2008) From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am J Clin Nutr 88(2):491S-499S
Nunn JD, Katz DR, Barker S et al (1986) Regulation of human tonsillar T-cell proliferation by the active metabolite of vitamin D3. Immunology 59(4):479–484
Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE (1999) An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell 96(4):507–15
Oksenberg JR (2013) Decoding multiple sclerosis: an update on genomics and future directions. Expert Rev Neurother. 13(12 Suppl):11–9. https://doi.org/10.1586/14737175.2013.865867
Orton S, Wald L, Confavreux C et al (2011) Association of UV radiation with multiple sclerosis prevalence and sex ratio in France. Neurology 76(5):425–431. https://doi.org/10.1212/WNL.0b013e31820a0a9f
Orton SM, Morris AP, Herrera BM, Ramagopalan SV, Lincoln MR, Chao MJ, Vieth R, Sadovnick AD, Ebers GC (2008) Evidence for genetic regulation of vitamin D status in twins with multiple sclerosis. Am J Clin Nutr 88(2):441–7
Orton SM, Ramagopalan SV, Para AE, Lincoln MR, Handunnetthi L, Chao MJ, Morahan J, Morrison KM, Sadovnick AD, Ebers GC (2011) Vitamin D metabolic pathway genes and risk of multiple sclerosis in Canadians. J Neurol Sci 305(1–2):116–20. https://doi.org/10.1016/j.jns.2011.02.032
Pierrot-Deseilligny C, Souberbielle J (2010) Is hypovitaminosis D one of the environmental risk factors for multiple sclerosis. Brain 133(7):1869–1888. https://doi.org/10.1093/brain/awq147
Prabhu AV, Luu W, Li D, Sharpe LJ, Brown AJ (2016) DHCR7: A vital enzyme switch between cholesterol and vitamin D production. Prog Lipid Res 64:138–151. https://doi.org/10.1016/j.plipres.2016.09.003
Pytel V, Matías-Guiu JA, Torre-Fuentes L, Montero-Escribano P, Maietta P, Botet J, Álvarez S, Gómez-Pinedo U, Matías-Guiu J (2019) Exonic variants of genes related to the vitamin D signaling pathway in the families of familial multiple sclerosis using whole-exome next generation sequencing. Brain Behav 9(4):e01272. https://doi.org/10.1002/brb3.1272
Ramagopalan SV, Dyment DA, Cader MZ, Morrison KM, Disanto G, Morahan JM, Berlanga-Taylor AJ, Handel A, De Luca GC, Sadovnick AD, Lepage P, Montpetit A, Ebers GC (2011) Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann Neurol 70(6):881–6. https://doi.org/10.1002/ana.22678
Ramagopalan SV, Yee IM, Dyment DA, Orton SM, Marrie RA, Sadovnick AD, Ebers GC (2009) Canadian collaborative study group parent-of-origin effect in multiple sclerosis: observations from interracial matings. Neurology 73(8):602–605. https://doi.org/10.1212/WNL.0b013e3181af33cf
Ramasamy A, Trabzuni D, Forabosco P, Smith C, Walker R, Dillman A, Sveinbjornsdottir S, North American Brain Expression Consortium (NABEC), UK Brain Expression Consortium (UKBEC), Hardy J, Weale ME, Ryten M (2014) Genetic evidence for a pathogenic role for the vitamin D3 metabolizing enzyme CYP24A1 in multiple sclerosis. Mult Scler Relat Disord 3(2):211–219
Rhead B, Bäärnhielm M, Gianfrancesco M, Mok A, Shao X, Quach H, Shen L, Schaefer C, Link J, Gyllenberg A, Hedström AK, Olsson T (2016) Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk. Neurol Genet 2(5):e97. https://doi.org/10.1212/NXG.0000000000000097
Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, Dilthey A, Su Z, Freeman C, Hunt SE, Edkins S et al (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2. Nature 476(7359):214–219. https://doi.org/10.1038/nature10251
Scazzone C, Agnello L, Ragonese P, Lo Sasso B, Bellia C, Bivona G, Schillaci R, Salemi G, Ciaccio M (2018) Association of CYP2R1 rs10766197 with MS risk and disease progression. J Neurosci Res 96(2):297–304. https://doi.org/10.1002/jnr.24133
Simon KC, Munger KL, Yang Xing, Ascherio A (2010) Polymorphisms in vitamin D metabolism related genes and risk of multiple sclerosis. Mult Scler 16(2):133–8. https://doi.org/10.1177/1352458509355069
Sioka C, Papakonstantinou S, Markoula S, Gkartziou F, Georgiou A, Georgiou I, Pelidou SH, Kyritsis AP, Fotopoulos A (2011) Vitamin D receptor gene polymorphisms in multiple sclerosis patients in northwest Greece. J Negat Results Biomed 10:3. https://doi.org/10.1186/1477-5751-10-3
Smolders J, Damoiseaux J, Menheere P, Tervaert JW, Hupperts R (2009) Fok-I vitamin D receptor gene polymorphism (rs10735810) and vitamin D metabolism in multiple sclerosis. J Neuroimmunol 207(1–2):117–21. https://doi.org/10.1016/j.jneuroim.2008.12.011
Soilu-Hänninen M, Laaksonen M, Laitinen I, Erälinna JP, Lilius EM, Mononen I (2008) 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 79(2):152–7
Steckley JL, Dyment DA, Sadovnick AD, Risch N, Hayes C, Ebers GC (2000) Genetic analysis of vitamin D related genes in Canadian multiple sclerosis patients. Canadian Collaborative Study Group. Neurology 54(3):729–32
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):1349–52. https://doi.org/10.1038/ejhg.2010.113
Tajouri L, Ovcaric M, Curtain R, Johnson MP, Griffiths LR, Csurhes P, Pender MP, Lea RA (2005) Variation in the vitamin D receptor gene is associated with multiple sclerosis in an Australian population. J Neurogenet 19(1):25–38
Tiwari S, Lapierre J, Ojha CR, Martins K, Parira T, Dutta RK, Caobi A, Garbinski L, Ceyhan Y, Esteban-Lopez M, El-Hage N (2018) Signaling pathways and therapeutic perspectives related to environmental factors associated with multiple sclerosis. J Neurosci Res 96(12):1831–1846. https://doi.org/10.1002/jnr.24322
Tsuprykov O, Chen X, Hocher CF, Skoblo R, Yin L, Hocher B (2018) Why should we measure free 25(OH) vitamin D? J Steroid Biochem Mol Biol 180:87–104. https://doi.org/10.1016/j.jsbmb.2017.11.014
Ueda P, Rafatnia F, Bäärnhielm M, Fröbom R, Korzunowicz G, Lönnerbro R, Hedström AK, Eyles D, Olsson T, Alfredsson L (2014) Neonatal vitamin D status and risk of multiple sclerosis. Ann Neurol 76(3):338–46. https://doi.org/10.1002/ana.24210
van der Mei I, Ponsonby A, Blizzard L, Dwyer T (2001) Regional variation in multiple sclerosis prevalence in Australia and its association with ambient ultraviolet radiation. Neuroepidemiology 20(3):168–174. https://doi.org/10.1159/000054783
van der Mei IA, Ponsonby AL, Dwyer T, Blizzard L, Taylor BV, Kilpatrick T, Butzkueven H, McMichael AJ (2007) Vitamin D levels in people with multiple sclerosis and community controls in Tasmania. Australia. J Neurol 254(5):581–90
Vivona N, Bivona G, Noto D, Sasso BL, Cefalù AB, Chiarello G, Falletta A, Ciaccio M, Averna MR (2009) C-reactive protein but not soluble CD40 ligand and homocysteine is associated to common atherosclerotic risk factors in a cohort of coronary artery disease patients. Clin Biochem 42(16–17):1713–8. https://doi.org/10.1016/j.clinbiochem.2009.08.014
Vukusic S, Van Bockstael V, Gosselin S, Confavreux C (2006) Regional variations in the prevalence of multiple sclerosis in French farmers. J Neurol Neurosurg Psychiatr 78(7):707–709. https://doi.org/10.1136/jnnp.2006.101196
Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, Peltonen L, Cooper JD, O’Reilly PF et al (2010) Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376(9736):180–8. https://doi.org/10.1016/S0140-6736(10)60588-0
Wassif CA, Zhu P, Kratz L, Krakowiak PA, Battaile KP, Weight FF, Grinberg A, Steiner RD, Nwokoro NA, Kelley RI, Stewart RR, Porter FD (2001) Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith–Lemli–Opitz syndrome. Hum Mol Genet 10(6):555–64
Westerlind H, Ramanujam R, Uvehag D, Kuja-Halkola R, Boman M, Bottai M, Lichtenstein P, Hillert J (2014) Modest familial risks for multiple sclerosis: a registry-based study of the population of Sweden. Brain 137(Pt 3):770–8. https://doi.org/10.1093/brain/awt356
Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC (2003) Canadian Collaborative Study Group. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci USA 100(22):12877–82
Yamout B, Karaky NM, Mahfouz RA, Jaber F, Estaitieh N, Shamaa D, Abbas F, Hoteit R, Daher RT (2016) Vitamin D receptor biochemical and genetic profiling and HLA-class II genotyping among Lebanese with multiple sclerosis - A pilot study. J Neuroimmunol 293:59–64. https://doi.org/10.1016/j.jneuroim.2016.02.008
Yucel FE, Kamıslı O, Acar C, Sozen M, Tecellioğlu M, Ozcan C (2018) Analysis of Vitamin D receptor polymorphisms in patients with familial multiple sclerosis. Med Arc 72(1):58–61. https://doi.org/10.5455/medarh.2017.72.58-61
Zhang YJ, Zhang L, Chen SY, Yang GJ, Huang XL, Duan Y, Yang LJ, Ye DQ, Wang J (2018) Association between VDR polymorphisms and multiple sclerosis: systematic review and updated meta-analysis of case-control studies. Neurol Sci 39(2):225–234. https://doi.org/10.1007/s10072-017-3175-3
Zhu JG, Ochalek JT, Kaufmann M, Jones G, Deluca HF (2013) CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo. Proc Natl Acad Sci U S A 110(39):15650–5. https://doi.org/10.1073/pnas.1315006110
Zhuang JC, Huang ZY, Zhao GX, Yu H, Li ZX, Wu ZY (2015) Variants of CYP27B1 are associated with both multiple sclerosis and neuromyelitis optica patients in Han Chinese population. Gene 557(2):236–9. https://doi.org/10.1016/j.gene.2014.12.045
Zinellu A, Sotgia S, Porcu P et al (2011) Carotid restenosis is associated with plasma ADMA concentrations in carotid endarterectomy patients. Clin Chem Lab Med 49(5):897–901. https://doi.org/10.1515/CCLM.2011.121
Zou L, Porter TD (2015) Rapid suppression of 7-dehydrocholesterol reductase activity in keratinocytes by vitamin D. J Steroid Biochem Mol Biol 148:64–71. https://doi.org/10.1016/j.jsbmb.2014.12.00
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Scazzone, C., Agnello, L., Bivona, G. et al. Vitamin D and Genetic Susceptibility to Multiple Sclerosis. Biochem Genet 59, 1–30 (2021). https://doi.org/10.1007/s10528-020-10010-1
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DOI: https://doi.org/10.1007/s10528-020-10010-1