The Open Biochemistry Journal




ISSN: 1874-091X ― Volume 14, 2020
REVIEW ARTICLE

Vitamin D and Multiple Sclerosis: An Open-Ended Story



Concetta Scazzone1, *, Luisa Agnello1, *, Bruna Lo Sasso1, Anna Maria Ciaccio2, Rosaria V Giglio1, Giulia Bivona1, #, Marcello Ciaccio1, 3, #, *
1 Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy
2 University of Palermo, Palermo, Italy
3 Department of Laboratory Medicine, University of Palermo, Palermo, Italy

Abstract

Multiple Sclerosis (MS) is a chronic inflammatory autoimmune disease of the Central Nervous System (CNS). Genetic, epigenetic and environmental factors interact together, contributing to the complex pathogenesis of the disease. In the last decades, the role of hypovitaminosis D on MS risk was hypothesised. Several factors drive the regulation of vitamin D status, including genetics. The current review summarises the literature evidence on the association between vitamin D and MS, with a focus on the genetic polymorphisms in vitamin D-related genes. The variants of the genes codifying Vitamin D Receptor (VDR), Vitamin D Binding Protein (VDBP) and CYP enzymes have been investigated, but the findings are controversial. Only a few studies have addressed the role of DHCR7 polymorphisms in MS risk.

Keywords: Vitamin D, Genetic, Genes, SNP, Multiple sclerosis, Susceptibility.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 13
First Page: 88
Last Page: 98
Publisher Id: TOBIOCJ-13-88
DOI: 10.2174/1874091X01913010088

Article History:

Received Date: 25/09/2019
Revision Received Date: 09/12/2019
Acceptance Date: 13/12/2019
Electronic publication date: 31/12/2019
Collection year: 2019

© 2019 Scazzone et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at Department of Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Italy, Via del Vespro, 129, CAP 90127, Palermo, Sicily, Italy; Tel: 0039 09123865707 Email: marcello.ciaccio@unipa.it
* Concetta Scazzone and Luisa Agnello are both considered first authors
# Giulia Bivona and Marcello Ciaccio are both considered last authors.






1. INTRODUCTION

Multiple Sclerosis (MS) is an autoimmune disease of the Central Nervous System (CNS). The triad consisting of inflammation, demyelination and neuroaxonal damage in the CNS causes clinical disability, characterised by a wide spectrum of signs and symptoms. MS is a multifactorial disease, the pathogenesis of which is the result of the interaction among genetic, epigenetic and environmental factors [1Baranzini, S.E.; Oksenberg, J.R. The genetics of multiple sclerosis: From 0 to 200 in 50 years. Trends Genet., 2017, 33(12), 960-970.
[http://dx.doi.org/10.1016/j.tig.2017.09.004] [PMID: 28987266]
].

In the last decades, hypovitaminosis D has emerged as a risk factor for MS. Initially, since vitamin D is mainly produced in the skin by the action of Ultraviolet (UV) radiation [2Norman, A.W. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am. J. Clin. Nutr., 2008, 88(2), 491S-499S.
[http://dx.doi.org/10.1093/ajcn/88.2.491S] [PMID: 18689389]
], it was proposed as the scapegoat to explain the association between reduced solar radiation exposure and increased risk of developing MS. Indeed, an inverse correlation between geographical latitude and MS prevalence, with increasing risk from the equator to North and South Poles, has been reported [3Beretich, B.D.; Beretich, T.M. Explaining multiple sclerosis prevalence by ultraviolet exposure: A geospatial analysis. Mult. Scler., 2009, 15(8), 891-898.
[http://dx.doi.org/10.1177/1352458509105579] [PMID: 19667017]
]. However, this hypothesis is still debated. Koch-Henriksen and Sørensen reported a latitudinal gradient of incidence of MS in Europe and North America, but not in Australia and New Zealand [4Koch-Henriksen, N.; Sorensen, P.S. Why does the north-south gradient of incidence of multiple sclerosis seem to have disappeared on the northern hemisphere? J. Neurol. Sci., 2011, 311(1-2), 58-63.
[http://dx.doi.org/10.1016/j.jns.2011.09.003] [PMID: 21982346]
]. Also, Bezzini and Battaglia observed an inverse correlation between MS and latitude in Europe [5Bezzini, D.; Battaglia, M.A. Multiple sclerosis epidemiology in europe. Adv. Exp. Med. Biol., 2017, 958, 141-159.
[http://dx.doi.org/10.1007/978-3-319-47861-6_9] [PMID: 28093712]
]. However, they concluded that the increasing prevalence could be the result of increasing survival and incidence. Overall, many profound cultural, economic, and, sociological differences between northern and southern Europe can influence the geographical distribution of MS; for instance, viral and fungal infections may be related to MS spreading among selected individuals, including drug users and homosexuals/bisexuals [6Benito-León, J.; Laurence, M. The role of fungi in the etiology of multiple sclerosis. Front. Neurol., 2017, 8, 535.
[http://dx.doi.org/10.3389/fneur.2017.00535] [PMID: 29085329]
, 7Roe, C. HIV immunodynamics and multiple sclerosis. J Neurovirol, 2016, 22, 254-5.
[http://dx.doi.org/10.1007/s13365-015-0381-8]
]. In particular, Benito-Leon and Laurence suggested that MS could be due to a fungal pathogen because vitamin D related gene variants are involved in fungal diseases [6Benito-León, J.; Laurence, M. The role of fungi in the etiology of multiple sclerosis. Front. Neurol., 2017, 8, 535.
[http://dx.doi.org/10.3389/fneur.2017.00535] [PMID: 29085329]
].

Collective data from epidemiological, clinical and experimental studies suggest that genetics also contribute to the vitamin D status, with an estimated heritability ranging from 23 to 80% [8Dastani, Z.; Li, R.; Richards, B. Genetic regulation of vitamin D levels. Calcif. Tissue Int., 2013, 92(2), 106-117.
[http://dx.doi.org/10.1007/s00223-012-9660-z] [PMID: 23114382]
]. In particular, genetic studies disclosed several Single Nucleotide Polymorphisms (SNPs) in the genes codifying molecules involved in the vitamin D pathway associated with the vitamin D status. Accordingly, several authors investigated the influence of these SNPs on MS risk.

The current review summarises the literature evidence on the association between vitamin D status and MS risk.

2. VITAMIN D

2.1. Metabolism

Vitamin D, either in D2 or D3 form, is a secosteroid prohormone. Vitamin D3 is mainly produced endogenously in the skin where Ultraviolet B (UVB) rays convert 7Dehydrocholesterol (7DHC) into pre-vitamin D3 that, spontaneously, isomerizes into vitamin D3. However, it can be also introduced exogenously [9Bivona, G.; Agnello, L.; Lo Sasso, B.; Scazzone, C.; Butera, D.; Gambino, C.M.; Iacolino, G.; Bellia, C.; Ciaccio, M. Vitamin D in malaria: more hypotheses than clues. Heliyon, 2019, 5(2)e01183
[http://dx.doi.org/10.1016/j.heliyon.2019.e01183] [PMID: 30793054]
-11Prabhu, A.V.; Luu, W.; Sharpe, L.J.; Brown, A.J. Cholesterol-mediated degradation of 7-Dehydrocholesterol reductase switches the balance from cholesterol to vitamin D synthesis. J. Biol. Chem., 2016, 291(16), 8363-8373.
[http://dx.doi.org/10.1074/jbc.M115.699546] [PMID: 26887953]
]. Vitamin D2 is produced by UVB radiation of the ergosterol in fungi; it can be introduced in humans by the diet, including food, supplementation and fortification [12Christakos, S.; Dhawan, P.; Verstuyf, A.; Verlinden, L.; Carmeliet, G.; Vitamin, D. Vitamin D: Metabolism, molecular mechanism of action, and pleiotropic effects. Physiol. Rev., 2016, 96(1), 365-408.
[http://dx.doi.org/10.1152/physrev.00014.2015] [PMID: 26681795]
]. Vitamin D3, both endogenous and exogenous, as well as vitamin D2, is a biologically inactive prohormone that becomes an active hormone after two hydroxylation reactions. The first 25-hydroxylation reaction takes place in the liver and produces 25-hydroxyl-vitamin-D2 [25(OH)D2] and 25-hydroxyl-vitamin -D3 [25(OH)D3]. The second hydroxylation reaction converts 25(OH)D2 and D3 in the biologically active form, 1,25-dihydroxy-vitamin-D2 [1,25(OH)D2] and 1,25-dihydroxy-vitamin-D3 [1,25(OH)D3]; this reaction occurs mainly in the kidney proximal tubule cells. From now, the terms 25(OH)D and 1,25(OH)2D will be used to indicate the sum of D2 and D3 metabolites. Vitamin D binding protein (VDBP) binds both 25(OH)D and 1,25(OH)2D with high affinity [13Tsuprykov, O.; Chen, X.; Hocher, C.F.; Skoblo, R.; Lianghong Yin, ; Hocher, B. Why should we measure free 25(OH) vitamin D? J. Steroid Biochem. Mol. Biol., 2018, 180, 87-104.
[http://dx.doi.org/10.1016/j.jsbmb.2017.11.014] [PMID: 29217467]
].

1,25(OH)2D exerts both genomic and non-genomic actions through the interaction with vitamin D receptor (VDR) and Membrane-Associated Rapid Response Steroid-Binding proteins (MARRS), respectively [14Bikle, D.D. Vitamin D metabolism, mechanism of action, and clinical applications. Chem. Biol., 2014, 21(3), 319-329.
[http://dx.doi.org/10.1016/j.chembiol.2013.12.016] [PMID: 24529992]
]. Besides its role in calcium metabolism, it is now widely known that vitamin D exerts several pleiotropic effects regulating different biological functions, including the immune response.

Vitamin D catabolism depends on carbons C-24 and C-23 hydroxylation reactions.

The three main steps in vitamin D metabolism, namely 25-hydroxylation, 1α-hydroxylation, and 24-hydroxylation, are all executed by cytochrome P450 enzymes (CYPs) [14Bikle, D.D. Vitamin D metabolism, mechanism of action, and clinical applications. Chem. Biol., 2014, 21(3), 319-329.
[http://dx.doi.org/10.1016/j.chembiol.2013.12.016] [PMID: 24529992]
, 15Caruso, A.; Bellia, C.; Pivetti, A.; Agnello, L.; Bazza, F.; Scazzone, C.; Bivona, G.; Lo Sasso, B.; Ciaccio, M. Effects of EPHX1 and CYP3A4 polymorphisms on carbamazepine metabolism in epileptic patients. Pharm. Genomics Pers. Med., 2014, 7, 117-120.
[http://dx.doi.org/10.2147/PGPM.S55548] [PMID: 24817818]
]. (Fig. 1) shows the metabolic pathway of vitamin D.

Vitamin D, both D2 and D3, can be either synthetized in the skin or absorbed by enterocytes forming cholecalciferol. It becomes active Vitamin D after two hydroxylations steps. The first hydroxylation occurs in the liver producing 25(OH)D; the second hydroxylation takes place in the kidney and in extra-renal cells and produces the biologically active form of vitamin D, 1,25(OH)2D. The latter exerts its biological actions through the interaction with the intracellular receptor VDR or the transmembrane receptor MARRS.

2.2. Vitamin D Status and its Heritability

Vitamin D status is assessed in clinical practice by the measurement of serum 25(OH)D levels, which are considered the best indicator of circulating vitamin D. The reasons for this can be summarised as follows: i) 25(OH)D has a longer half-life than 1,25(OH)2D (2–3 weeks vs 4-6 hours); ii) while 25(OH)D levels are unregulated, 1,25(OH)2D levels are tightly regulated and strictly kept between limits even when adverse effects start to occur; iii) 1,25(OH)2D can be produced both in the kidney cells and in many other cells. The extra-renal 1,25(OH)2D does not enter into the circulation, but it acts locally. Thus, serum 1,25(OH)2D does not reflect the total 1,25(OH)2D. In contrast, circulating 25(OH)D mirrors 25(OH)D reserve prior to the conversion, also including the available substrate for the extra-renal 1,25(OH)2D synthesis [16Niek, F. Dirks, Mariëtte T. Ackermans, Paul Lips, Renate T. de Jongh, Marc G. Vervloet, Robert de Jonge, Annemieke C. Heijboer. The When, What & How of Measuring Vitamin D Metabolism in Clinical Medicine. Nutrients, 2018, 10, 482.
[http://dx.doi.org/10.3390/nu10040482]
].

Extensive research over the past decades has suggested that genetics greatly influences vitamin D status [4Koch-Henriksen, N.; Sorensen, P.S. Why does the north-south gradient of incidence of multiple sclerosis seem to have disappeared on the northern hemisphere? J. Neurol. Sci., 2011, 311(1-2), 58-63.
[http://dx.doi.org/10.1016/j.jns.2011.09.003] [PMID: 21982346]
], as reported by twin and family studies. To date, numerous variants in genes codifying molecules involved in the vitamin D metabolism and associated with altered circulating vitamin D levels have been identified. This evidence is derived from genetic studies based mainly on two different approaches: candidate gene study and Genome Wide Association Study (GWAS) [4Koch-Henriksen, N.; Sorensen, P.S. Why does the north-south gradient of incidence of multiple sclerosis seem to have disappeared on the northern hemisphere? J. Neurol. Sci., 2011, 311(1-2), 58-63.
[http://dx.doi.org/10.1016/j.jns.2011.09.003] [PMID: 21982346]
]. The candidate gene approach is based on the selection of a gene depending on the knowledge of the metabolic pathway or pathogenesis disease. GWAS, instead, is a hypothesis-free approach that evaluates the entire genome to identify allelic variants that are associated with a specific trait [17Di Resta, C.; Ferrari, M. Next generation sequencing: From research area to clinical practice. EJIFCC, 2018, 29(3), 215-220.
[PMID: 30479607]
, 18Kricka, L.J.; Di Resta, C. Translating genes into health. Nat. Genet., 2013, 45(1), 4-5.
[http://dx.doi.org/10.1038/ng.2510] [PMID: 23268128]
]. Both the approaches have advantages and disadvantages that have been well summarised in the review by Lin [19Lin, R.; Charlesworth, J.; van der Mei, I.; Taylor, B.V. The genetics of multiple sclerosis. Pract. Neurol., 2012, 12(5), 279-288.
[http://dx.doi.org/10.1136/practneurol-2012-000276] [PMID: 22976058]
]. However, both are pivotal in understanding the genetics of vitamin D status.

3. MULTIPLE SCLEROSIS

MS represents a common neurological disease in young adultswhich is usually diagnosed between the third and fifth decade of life. It is characterized by sexual dimorphism influencing both the incidence and severity of the disease. In particular, the prevalence is higher in women than in men, with a female to male ratio of 2:1-3:1, and a “maternal parent-of-origin” effect. However, men present an overall worse course of the disease, with a rapid accrual of disability and progression [20Golden, L.C.; Voskuhl, R. The importance of studying sex differences in disease: The example of multiple sclerosis. J. Neurosci. Res., 2017, 95(1-2), 633-643.
[http://dx.doi.org/10.1002/jnr.23955] [PMID: 27870415]
].

MS is an immune-mediated disease characterized by the gradual destruction of myelin due to an autoimmune response against self-antigens [21Tiwari, S.; Lapierre, J.; Ojha, C.R.; Martins, K.; Parira, T.; Dutta, R.K.; Caobi, A.; Garbinski, L.; Ceyhan, Y.; Esteban-Lopez, M.; El-Hage, N. Signaling pathways and therapeutic perspectives related to environmental factors associated with multiple sclerosis. J. Neurosci. Res., 2018, 96(12), 1831-1846.
[http://dx.doi.org/10.1002/jnr.24322] [PMID: 30204260]
]. The characteristic pathological hallmark of MS is the inflammation in the CNS, leading to demyelinating plaques localized mainly in the periventricular area, pons and spinal cord [22Dobson, R.; Giovannoni, G. Multiple sclerosis - A review. Eur. J. Neurol., 2019, 26(1), 27-40.
[http://dx.doi.org/10.1111/ene.13819] [PMID: 30300457]
]. MS has long been considered a T cell-mediated inflammatory disease [23Rostami, A.; Ciric, B. Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination. J. Neurol. Sci., 2013, 333(1-2), 76-87.
[http://dx.doi.org/10.1016/j.jns.2013.03.002] [PMID: 23578791]
, 24Zozulya, A.L.; Wiendl, H. The role of regulatory T cells in multiple sclerosis. Nat. Clin. Pract. Neurol., 2008, 4(7), 384-398.
[http://dx.doi.org/10.1038/ncpneuro0832] [PMID: 18578001]
]. However, the detection of the Oligoclonal Band (OCB) in the CSF of MS patients and the success of B-cell targeted therapies challenge the standard T-cell autoimmune dogma [25Lehmann-Horn, K.; Kinzel, S.; Weber, M.S. Deciphering the role of B cells in multiple sclerosis-towards specific targeting of pathogenic function. Int. J. Mol. Sci., 2017, 18(10)E2048
[http://dx.doi.org/10.3390/ijms18102048] [PMID: 28946620]
]. Studies on Experimental Autoimmune Encephalomyelitis (EAE), which represents the best animal model of MS, have made a great contribution to understanding the pathogenesis of MS. It is now well documented that both CD4 and CD8 T lymphocytes and their related cytokines, as well as B-lymphocytes, take part in the development of MS. Among CD4 T cells, activated myelin-specific T helper (Th)1 and Th17 with their related cytokines, such as interferon-gamma (IFN-γ), interleukin (IL)-17, IL-22 and granulocite-macrophage colony-stimulating factor (GM-CSF), play a pivotal role in initiating the inflammation in the CNS [26Fletcher, J.M.; Lalor, S.J.; Sweeney, C.M.; Tubridy, N.; Mills, K.H. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin. Exp. Immunol., 2010, 162(1), 1-11.
[http://dx.doi.org/10.1111/j.1365-2249.2010.04143.x] [PMID: 20682002]
, 27Legroux, L.; Arbour, N. Multiple sclerosis and T lymphocytes: An entangled story. J. Neuroimmune Pharmacol., 2015, 10(4), 528-546.
[http://dx.doi.org/10.1007/s11481-015-9614-0] [PMID: 25946987]
]. B-lymphocytes contribute to the MS pathogenesis through different mechanisms including the production of antibody-producing plasma cells, potent Antigen-Presenting Cells (APC) and secretion of pro-inflammatory cytokines [25Lehmann-Horn, K.; Kinzel, S.; Weber, M.S. Deciphering the role of B cells in multiple sclerosis-towards specific targeting of pathogenic function. Int. J. Mol. Sci., 2017, 18(10)E2048
[http://dx.doi.org/10.3390/ijms18102048] [PMID: 28946620]
]. Moreover, chronic stages of MS are characterized by a compartmentalized immune response in the CNS with activated microglia and macrophages [28Sospedra, M.; Martin, R. Immunology of Multiple Sclerosis. Semin. Neurol., 2016, 36(2), 115-127.
[http://dx.doi.org/10.1055/s-0036-1579739] [PMID: 27116718]
].

Although MS is not a hereditary disease, genetic predisposition increases the risk of developing it [29Willer, C.J.; Dyment, D.A.; Risch, N.J.; Sadovnick, A.D.; Ebers, G.C. Canadian Collaborative Study Group. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc. Natl. Acad. Sci. USA, 2003, 100(22), 12877-12882.
[http://dx.doi.org/10.1073/pnas.1932604100] [PMID: 14569025]
-31Westerlind, H.; Ramanujam, R.; Uvehag, D.; Kuja-Halkola, R.; Boman, M.; Bottai, M.; Lichtenstein, P.; Hillert, J. Modest familial risks for multiple sclerosis: a registry-based study of the population of Sweden. Brain, 2014, 137(Pt 3), 770-778.
[http://dx.doi.org/10.1093/brain/awt356] [PMID: 24441172]
]. A meta-analysis of twins revealed that genetic alterations could at least partly explain individual differences in MS susceptibility [32Fagnani, C.; Neale, M.C.; Nisticò, L.; Stazi, M.A.; Ricigliano, V.A.; Buscarinu, M.C.; Salvetti, M.; Ristori, G. Twin studies in multiple sclerosis: A meta-estimation of heritability and environmentality. Mult. Scler., 2015, 21(11), 1404-1413.
[http://dx.doi.org/10.1177/1352458514564492] [PMID: 25583848]
]. Epidemiological studies suggested that the individual risk for subjects with a family member affected increases proportionally to the degree of kinship and, consequently, to the percentage of shared genetic background, being the highest among monozygotic twins (25-30%) and greatly decreasing in siblings (5%), parents (2%) and distant relatives (1%) [33Ghasemi, N.; Razavi, S.; Nikzad, E. Multiple sclerosis: Pathogenesis, symptoms, diagnoses and cell-based therapy. Cell J., 2017, 19(1), 1-10.
[http://dx.doi.org/10.22074/cellj.2016.4867] [PMID: 28367411]
]. The Common-Disease-Common Variant (CD-CV) hypothesis seems to be the best model to explain MS heritability [34Didonna, A.; Oksenberg, J.R. Genetic determinants of risk and progression in multiple sclerosis. Clin. Chim. Acta, 2015, 449, 16-22.
[http://dx.doi.org/10.1016/j.cca.2015.01.034] [PMID: 25661088]
]. According to this model, MS risk is the consequence of the cumulating effects of numerous allelic variants, which are common in the general population.

Genetic studies revealed variants in several genes associated with MS, including those codifying molecules involved in vitamin D metabolism. CYP27B1 and CYP24A1 were the first genes involved in vitamin D metabolism identified by a GWAS, including 9772 MS and 17376 controls [35Sawcer, S.; Hellenthal, G.; Pirinen, M.; Spencer, C.C.; Patsopoulos, N.A.; Moutsianas, L.; Dilthey, A.; Su, Z.; Freeman, C.; Hunt, S.E.; Edkins, S.; Gray, E.; Booth, D.R.; Potter, S.C.; Goris, A.; Band, G.; Oturai, A.B.; Strange, A.; Saarela, J.; Bellenguez, C.; Fontaine, B.; Gillman, M.; Hemmer, B.; Gwilliam, R.; Zipp, F.; Jayakumar, A.; Martin, R.; Leslie, S.; Hawkins, S.; Giannoulatou, E.; D’alfonso, S.; Blackburn, H.; Martinelli Boneschi, F.; Liddle, J.; Harbo, H.F.; Perez, M.L.; Spurkland, A.; Waller, M.J.; Mycko, M.P.; Ricketts, M.; Comabella, M.; Hammond, N.; Kockum, I.; McCann, O.T.; Ban, M.; Whittaker, P.; Kemppinen, A.; Weston, P.; Hawkins, C.; Widaa, S.; Zajicek, J.; Dronov, S.; Robertson, N.; Bumpstead, S.J.; Barcellos, L.F.; Ravindrarajah, R.; Abraham, R.; Alfredsson, L.; Ardlie, K.; Aubin, C.; Baker, A.; Baker, K.; Baranzini, S.E.; Bergamaschi, L.; Bergamaschi, R.; Bernstein, A.; Berthele, A.; Boggild, M.; Bradfield, J.P.; Brassat, D.; Broadley, S.A.; Buck, D.; Butzkueven, H.; Capra, R.; Carroll, W.M.; Cavalla, P.; Celius, E.G.; Cepok, S.; Chiavacci, R.; Clerget-Darpoux, F.; Clysters, K.; Comi, G.; Cossburn, M.; Cournu-Rebeix, I.; Cox, M.B.; Cozen, W.; Cree, B.A.; Cross, A.H.; Cusi, D.; Daly, M.J.; Davis, E.; de Bakker, P.I.; Debouverie, M.; D’hooghe, M.B.; Dixon, K.; Dobosi, R.; Dubois, B.; Ellinghaus, D.; Elovaara, I.; Esposito, F.; Fontenille, C.; Foote, S.; Franke, A.; Galimberti, D.; Ghezzi, A.; Glessner, J.; Gomez, R.; Gout, O.; Graham, C.; Grant, S.F.; Guerini, F.R.; Hakonarson, H.; Hall, P.; Hamsten, A.; Hartung, H.P.; Heard, R.N.; Heath, S.; Hobart, J.; Hoshi, M.; Infante-Duarte, C.; Ingram, G.; Ingram, W.; Islam, T.; Jagodic, M.; Kabesch, M.; Kermode, A.G.; Kilpatrick, T.J.; Kim, C.; Klopp, N.; Koivisto, K.; Larsson, M.; Lathrop, M.; Lechner-Scott, J.S.; Leone, M.A.; Leppä, V.; Liljedahl, U.; Bomfim, I.L.; Lincoln, R.R.; Link, J.; Liu, J.; Lorentzen, A.R.; Lupoli, S.; Macciardi, F.; Mack, T.; Marriott, M.; Martinelli, V.; Mason, D.; McCauley, J.L.; Mentch, F.; Mero, I.L.; Mihalova, T.; Montalban, X.; Mottershead, J.; Myhr, K.M.; Naldi, P.; Ollier, W.; Page, A.; Palotie, A.; Pelletier, J.; Piccio, L.; Pickersgill, T.; Piehl, F.; Pobywajlo, S.; Quach, H.L.; Ramsay, P.P.; Reunanen, M.; Reynolds, R.; Rioux, J.D.; Rodegher, M.; Roesner, S.; Rubio, J.P.; Rückert, I.M.; Salvetti, M.; Salvi, E.; Santaniello, A.; Schaefer, C.A.; Schreiber, S.; Schulze, C.; Scott, R.J.; Sellebjerg, F.; Selmaj, K.W.; Sexton, D.; Shen, L.; Simms-Acuna, B.; Skidmore, S.; Sleiman, P.M.; Smestad, C.; Sørensen, P.S.; Søndergaard, H.B.; Stankovich, J.; Strange, R.C.; Sulonen, A.M.; Sundqvist, E.; Syvänen, A.C.; Taddeo, F.; Taylor, B.; Blackwell, J.M.; Tienari, P.; Bramon, E.; Tourbah, A.; Brown, M.A.; Tronczynska, E.; Casas, J.P.; Tubridy, N.; Corvin, A.; Vickery, J.; Jankowski, J.; Villoslada, P.; Markus, H.S.; Wang, K.; Mathew, C.G.; Wason, J.; Palmer, C.N.; Wichmann, H.E.; Plomin, R.; Willoughby, E.; Rautanen, A.; Winkelmann, J.; Wittig, M.; Trembath, R.C.; Yaouanq, J.; Viswanathan, A.C.; Zhang, H.; Wood, N.W.; Zuvich, R.; Deloukas, P.; Langford, C.; Duncanson, A.; Oksenberg, J.R.; Pericak-Vance, M.A.; Haines, J.L.; Olsson, T.; Hillert, J.; Ivinson, A.J.; De Jager, P.L.; Peltonen, L.; Stewart, G.J.; Hafler, D.A.; Hauser, S.L.; McVean, G.; Donnelly, P.; Compston, A. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature, 2011, 476(7359), 214-219.
[http://dx.doi.org/10.1038/nature10251] [PMID: 21833088]
]. This finding further supported the importance of vitamin D in MS risk and represented the foundation for investigating the influence of variants in genes implicated in vitamin D metabolism, catabolism and function on MS.

4. VITAMIN D AND MULTIPLE SCLEROSIS

4.1. Pathogenic Role of Hypovitaminosis D in Multiple Sclerosis

Vitamin D has been long investigated in many inflammatory- based, neurological, autoimmune and infectious diseases either as a risk factor or biomarker of severity, along with other biomarkers [36Brance, M.L.; Miljevic, J.N.; Tizziani, R.; Taberna, M.E.; Grossi, G.P.; Toni, P.; Valentini, E.; Trepat, A.; Zaccardi, J.; Moro, J.; Finuci Curi, B.; Tamagnone, N.; Ramirez, M.; Severini, J.; Chiarotti, P.; Consiglio, F.; Piñeski, R.; Ghelfi, A.; Kilstein, J.; Street, E.; Moretti, D.; Oliveto, V.; Mariño, M.; Manera, J.; Brun, L.R. Serum 25-hydroxyvitamin D levels in hospitalized adults with community-acquired pneumonia. Clin. Respir. J., 2018, 12(7), 2220-2227.
[http://dx.doi.org/10.1111/crj.12792] [PMID: 29570946]
-40Bellia, C.; Zaninotto, M.; Cosma, C.; Agnello, L.; Lo Sasso, B.; Bivona, G.; Plebani, M.; Ciaccio, M. Definition of the upper reference limit of glycated albumin in blood donors from Italy. Clin. Chem. Lab. Med., 2017, 56(1), 120-125.
[http://dx.doi.org/10.1515/cclm-2017-0179] [PMID: 28586301]
]. In particular, 25(OH)D has been recently proposed as a serum biomarker in neurodegenerative disorders, together with cardiovascular and inflammatory markers [41Wang, X.; Zhang, S.; Lin, F.; Chu, W.; Yue, S. Elevated Galectin-3 Levels in the Serum of Patients With Alzheimer’s Disease. Am. J. Alzheimers Dis. Other Demen., 2015, 30(8), 729-732.
[http://dx.doi.org/10.1177/1533317513495107] [PMID: 23823143]
-51Vivona, N.; Bivona, G.; Noto, D.; Sasso, B.L.; Cefalù, A.B.; Chiarello, G.; Falletta, A.; Ciaccio, M.; Averna, M.R. 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., 2009, 42(16-17), 1713-1718.
[http://dx.doi.org/10.1016/j.clinbiochem.2009.08.014] [PMID: 19732763]
].

Compelling evidence from epidemiological studies, experimental studies on animal models, in vitro, observational clinical and genetic studies suggest a role of hypovitaminosis D on MS risk and progression [52Goldberg; P. Multiple sclerosis: vitamin D and calcium as environmental determinants of prevalence. Int. J. Environ. Stud., 1974, 6, 19-27.
[http://dx.doi.org/10.1080/00207237408709630]
-59Mokry, L.E.; Ross, S.; Ahmad, O.S.; Forgetta, V.; Smith, G.D.; Goltzman, D.; Leong, A.; Greenwood, C.M.; Thanassoulis, G.; Richards, J.B. Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study. PLoS Med., 2015, 12(8)e1001866
[http://dx.doi.org/10.1371/journal.pmed.1001866] [PMID: 26305103]
]. This evidence is supported by the immunoregulatory and neuroprotective function of vitamin D [60Bivona, G.; Agnello, L.; Ciaccio, M. The immunological implication of the new vitamin D metabolism. Cent. Eur. J. Immunol., 2018, 43(3), 331-334.
[http://dx.doi.org/10.5114/ceji.2018.80053] [PMID: 30588177]
].

Significantly, immune cells, including macrophages, T and B lymphocytes, express the enzymatic machinery required to metabolize vitamin D, namely CYP27B1 and CYP24A1, and the receptors making them sensitive to its action. In particular, vitamin D regulates the immune response through several mechanisms that can be summarised as follows: i) inhibition of the synthesis and secretion of pro-inflammatory cytokines; ii) inhibition of Th1 and Th17 cell differentiation; iii) promotion of regulatory T-cells (Tregs) and macrophages proliferation; iv) inhibition of proliferation and differentiation of plasma cells as well as antibody production by B cells. Consequently, hypovitaminosis D shifts the balance of the immune system toward a pro-inflammatory state [61Aranow, C. Vitamin D and the immune system. J. Investig. Med., 2011, 59(6), 881-886.
[http://dx.doi.org/10.2310/JIM.0b013e31821b8755] [PMID: 21527855]
, 62Bivona, G.; Agnello, L.; Ciaccio, M. Vitamin D and Immunomodulation: Is It Time to Change the Reference Values? Ann. Clin. Lab. Sci., 2017, 47(4), 508-510.
[PMID: 28801380]
]. Further details on the relationship among vitamin D, the immune system and MS are provided in a recent review by Lu et al. [63Lu, M.; Taylor, B.V.; Körner, H. Genomic Effects of the Vitamin D Receptor: Potentially the Link between Vitamin D, Immune Cells, and Multiple Sclerosis. Front. Immunol., 2018, 9, 477.
[http://dx.doi.org/10.3389/fimmu.2018.00477] [PMID: 29593729]
].

Vitamin D is also regarded as a neurosteroid [64Groves, N.J.; McGrath, J.J.; Burne, T.H. Vitamin D as a neurosteroid affecting the developing and adult brain. Annu. Rev. Nutr., 2014, 34, 117-141.
[http://dx.doi.org/10.1146/annurev-nutr-071813-105557] [PMID: 25033060]
]. Studies on CSF revealed that both 25(OH)D and VDBP are detectable within the CNS and most CNS cells, including neurons, astrocytes and microglia cells, express both VDR and CYP27B1 [65Holmøy, T.; Moen, S.M.; Gundersen, T.A.; Holick, M.F.; Fainardi, E.; Castellazzi, M.; Casetta, I. 25-hydroxyvitamin D in cerebrospinal fluid during relapse and remission of multiple sclerosis. Mult. Scler., 2009, 15(11), 1280-1285.
[http://dx.doi.org/10.1177/1352458509107008] [PMID: 19808741]
-69Mimura, L.A.; Chiuso-Minicucci, F.; Fraga-Silva, T.F.; Zorzella-Pezavento, S.F.; França, T.G.; Ishikawa, L.L.; Penitenti, M.; Ikoma, M.R.; Sartori, A. Association of myelin peptide with vitamin D prevents autoimmune encephalomyelitis development. Neuroscience, 2016, 317, 130-140.
[http://dx.doi.org/10.1016/j.neuroscience.2015.12.053] [PMID: 26762804]
]. Thus, all this evidence supports a direct action of vitamin D on some functions of the CNS. Some authors described the role of vitamin D in the myelination and remyelination processes [70Goudarzvand, M.; Javan, M.; Mirnajafi-Zadeh, J.; Mozafari, S.; Tiraihi, T. Vitamins E and D3 attenuate demyelination and potentiate remyelination processes of hippocampal formation of rats following local injection of ethidium bromide. Cell. Mol. Neurobiol., 2010, 30(2), 289-299.
[http://dx.doi.org/10.1007/s10571-009-9451-x] [PMID: 19768531]
-74Mowry, E.M.; Krupp, L.B.; Milazzo, M.; Chabas, D.; Strober, J.B.; Belman, A.L.; McDonald, J.C.; Oksenberg, J.R.; Bacchetti, P.; Waubant, E. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann. Neurol., 2010, 67(5), 618-624.
[http://dx.doi.org/10.1002/ana.21972] [PMID: 20437559]
]. As previously mentioned, MS is characterized by progressive demyelination. However, in the early stage of MS, demyelinated lesions undergo a partial remyelination process as shown by neuroimaging findings [71Franklin, R.J.; ffrench-Constant, C.; Edgar, J.M.; Smith, K.J. Neuroprotection and repair in multiple sclerosis. Nat. Rev. Neurol., 2012, 8(11), 624-634.
[http://dx.doi.org/10.1038/nrneurol.2012.200] [PMID: 23026979]
]. Some authors showed that vitamin D is involved in the demyelination/ remyelination process, by modulating the differentiation of the Oligodendrocyte Precursor Cells (OPC) [70Goudarzvand, M.; Javan, M.; Mirnajafi-Zadeh, J.; Mozafari, S.; Tiraihi, T. Vitamins E and D3 attenuate demyelination and potentiate remyelination processes of hippocampal formation of rats following local injection of ethidium bromide. Cell. Mol. Neurobiol., 2010, 30(2), 289-299.
[http://dx.doi.org/10.1007/s10571-009-9451-x] [PMID: 19768531]
]. Moreover, vitamin D stimulates microglia activation, promoting the clearance of myelin debris and favouring remyelination [72Kotter, M.R.; Li, W.W.; Zhao, C.; Franklin, R.J. Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J. Neurosci., 2006, 26(1), 328-332.
[http://dx.doi.org/10.1523/JNEUROSCI.2615-05.2006] [PMID: 16399703]
].

The inverse association between vitamin D and MS risk is supported by numerous observational studies conducted both on children and adults worldwide, from Australia to Europe [75Munger, K.L.; Hongell, K.; Åivo, J.; Soilu-Hänninen, M.; Surcel, H.M.; Ascherio, A. 25-Hydroxyvitamin D deficiency and risk of MS among women in the Finnish Maternity Cohort. Neurology, 2017, 89(15), 1578-1583.
[http://dx.doi.org/10.1212/WNL.0000000000004489] [PMID: 28904091]
-78Soilu-Hänninen, M.; Laaksonen, M.; Laitinen, I.; Erälinna, J.P.; Lilius, E.M.; 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(2), 152-157.
[http://dx.doi.org/10.1136/jnnp.2006.105320] [PMID: 17578859]
]. The causal relationship between hypovitaminosis D and MS susceptibility is also proved by Mendelian Randomization (MR) analysis [79Rhead, B.; Bäärnhielm, M.; Gianfrancesco, M.; Mok, A.; Shao, X.; Quach, H.; Shen, L.; Schaefer, C.; Link, J.; Gyllenberg, A.; Hedström, A.K.; Olsson, T.; Hillert, J.; Kockum, I.; Glymour, M.M.; Alfredsson, L.; Barcellos, L.F. Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk. Neurol. Genet., 2016, 2(5)e97
[http://dx.doi.org/10.1212/NXG.0000000000000097] [PMID: 27652346]
]. Usually, Randomized Controlled Trials (RCTs) represent the gold standard for exploring causal inference between certain exposures and disease. However, an MS prevention trial with vitamin D is impossible for several reasons, such as the low incidence of the disease in the population and a long follow-up starting from the prenatal period to the fourth decade of life [80Harroud, A.; Richards, J.B. Mendelian randomization in multiple sclerosis: A causal role for vitamin D and obesity? Mult. Scler., 2018, 24(1), 80-85.
[http://dx.doi.org/10.1177/1352458517737373] [PMID: 29307294]
]. Alternately, MR represents a powerful tool to verify the causal association between a certain trait, such as vitamin D, and an outcome, such as Multiple Sclerosis, based on genetic associations. Recently, three studies based on this epidemiological approach provided strong evidence of the causal role of low vitamin D levels in MS, even after accounting for other risk factors, such as smoking, and other potential confounders, such as sun exposure and diet [59Mokry, L.E.; Ross, S.; Ahmad, O.S.; Forgetta, V.; Smith, G.D.; Goltzman, D.; Leong, A.; Greenwood, C.M.; Thanassoulis, G.; Richards, J.B. Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study. PLoS Med., 2015, 12(8)e1001866
[http://dx.doi.org/10.1371/journal.pmed.1001866] [PMID: 26305103]
, 79Rhead, B.; Bäärnhielm, M.; Gianfrancesco, M.; Mok, A.; Shao, X.; Quach, H.; Shen, L.; Schaefer, C.; Link, J.; Gyllenberg, A.; Hedström, A.K.; Olsson, T.; Hillert, J.; Kockum, I.; Glymour, M.M.; Alfredsson, L.; Barcellos, L.F. Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk. Neurol. Genet., 2016, 2(5)e97
[http://dx.doi.org/10.1212/NXG.0000000000000097] [PMID: 27652346]
, 81Gianfrancesco, M.A.; Stridh, P.; Rhead, B.; Shao, X.; Xu, E.; Graves, J.S.; Chitnis, T.; Waldman, A.; Lotze, T.; Schreiner, T.; Belman, A.; Greenberg, B.; Weinstock-Guttman, B.; Aaen, G.; Tillema, J.M.; 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, T.C.; Shen, L.; Quach, H.; Quach, D.; Hillert, J.; Bäärnhielm, M.; Hedstrom, A.; Olsson, T.; Kockum, I.; Alfredsson, L.; Metayer, C.; Schaefer, C.; Barcellos, L.F.; Waubant, E. Network of Pediatric Multiple Sclerosis Centers. Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS. Neurology, 2017, 88(17), 1623-1629.
[http://dx.doi.org/10.1212/WNL.0000000000003849] [PMID: 28356466]
].

Another evidence supporting the pathogenic role of hypovitaminosis D in MS is that vitamin D could regulate most of the MS-associated genes through the interaction with the Vitamin D Responsive Elements (VDREs) located within their promoter region [82Ramagopalan, S.V.; Heger, A.; Berlanga, A.J.; Maugeri, N.J.; Lincoln, M.R.; Burrell, A.; Handunnetthi, L.; Handel, A.E.; Disanto, G.; Orton, S.M.; Watson, C.T.; Morahan, J.M.; Giovannoni, G.; Ponting, C.P.; Ebers, G.C.; Knight, J.C. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res., 2010, 20(10), 1352-1360.
[http://dx.doi.org/10.1101/gr.107920.110] [PMID: 20736230]
, 83Disanto, G.; Sandve, G.K.; Berlanga-Taylor, A.J.; Ragnedda, G.; Morahan, J.M.; Watson, C.T.; Giovannoni, G.; Ebers, G.C.; Ramagopalan, S.V. Vitamin D receptor binding, chromatin states and association with multiple sclerosis. Hum. Mol. Genet., 2012, 21(16), 3575-3586.
[http://dx.doi.org/10.1093/hmg/dds189] [PMID: 22595971]
].

Collectively, all these data support the role of hypovitaminosis D in MS. This lead to the investigation of the effect of vitamin D supplementation on MS. However, the findings have not been encouraging as shown by some authors [84Pozuelo-Moyano, B.; Benito-León, J.; Mitchell, A.J.; Hernández-Gallego, J. A systematic review of randomized, double-blind, placebo-controlled trials examining the clinical efficacy of vitamin D in multiple sclerosis. Neuroepidemiology, 2013, 40(3), 147-153.
[http://dx.doi.org/10.1159/000345122] [PMID: 23257784]
-86Røsjø, E.; Steffensen, L.H.; Jørgensen, L.; Lindstrøm, J.C.; Šaltytė Benth, J.; Michelsen, A.E.; Aukrust, P.; Ueland, T.; Kampman, M.T.; Torkildsen, Ø.; Holmøy, T. Vitamin D supplementation and systemic inflammation in relapsing-remitting multiple sclerosis. J. Neurol., 2015, 262(12), 2713-2721.
[http://dx.doi.org/10.1007/s00415-015-7902-5] [PMID: 26429571]
]. A recent meta-analysis reported inconclusive results showing no effect of vitamin D on clinical outcomes in MS patients [84Pozuelo-Moyano, B.; Benito-León, J.; Mitchell, A.J.; Hernández-Gallego, J. A systematic review of randomized, double-blind, placebo-controlled trials examining the clinical efficacy of vitamin D in multiple sclerosis. Neuroepidemiology, 2013, 40(3), 147-153.
[http://dx.doi.org/10.1159/000345122] [PMID: 23257784]
]. Other authors reported the effect of vitamin D supplementation on improving mental health in MS patients finding questionable results [85Allan, G.M.; Cranston, L.; Lindblad, A.; McCormack, J.; Kolber, M.R.; Garrison, S.; Korownyk, C.; Vitamin, D. Vitamin D: A Narrative Review Examining the Evidence for Ten Beliefs. J. Gen. Intern. Med., 2016, 31(7), 780-791.
[http://dx.doi.org/10.1007/s11606-016-3645-y] [PMID: 26951286]
]. Also, the effect of vitamin D supplementation on inflammatory markers has been studied in MS patients, resulting in no difference between vitamin D and the placebo group [86Røsjø, E.; Steffensen, L.H.; Jørgensen, L.; Lindstrøm, J.C.; Šaltytė Benth, J.; Michelsen, A.E.; Aukrust, P.; Ueland, T.; Kampman, M.T.; Torkildsen, Ø.; Holmøy, T. Vitamin D supplementation and systemic inflammation in relapsing-remitting multiple sclerosis. J. Neurol., 2015, 262(12), 2713-2721.
[http://dx.doi.org/10.1007/s00415-015-7902-5] [PMID: 26429571]
]. Thus, further studies are needed to clarify whether vitamin D supplementation could be useful in MS patients.

Fig (1)
Vitamin D metabolism.


4.2. Variants in Vitamin D Related-genes and Multiple Sclerosis

Polymorphisms in most of the genes involved in the vitamin D pathway have been investigated in MS. It should be noted that vitamin D related gene variants are associated with many biological phenomena, other than MS onset [6Benito-León, J.; Laurence, M. The role of fungi in the etiology of multiple sclerosis. Front. Neurol., 2017, 8, 535.
[http://dx.doi.org/10.3389/fneur.2017.00535] [PMID: 29085329]
].

7-dehydrocholesterol reductase (DHCR7) gene variants were first associated with hypovitaminosis D in 2010 by two independent GWAS [87Ahn, J; Yu, K; Stolzenberg-Solomon, R; Simon, KC; McCullough, ML; Gallicchio, L; Jacobs, EJ; Ascherio, A; Helzlsouer, K Hum. Mol, Genet., Genome-wide association study of circulating vitamin D levels, 2010, 19, 2739-45.
[http://dx.doi.org/10.1093/hmg/ddq155]
, 88Wang, T.J.; Zhang, F.; Richards, J.B.; Kestenbaum, B.; van Meurs, J.B.; Berry, D.; Kiel, D.P.; Streeten, E.A.; Ohlsson, C.; Koller, D.L.; Peltonen, L.; Cooper, J.D.; O’Reilly, P.F.; Houston, D.K.; Glazer, N.L.; Vandenput, L.; Peacock, M.; Shi, J.; Rivadeneira, F.; McCarthy, M.I.; Anneli, P.; de Boer, I.H.; Mangino, M.; Kato, B.; Smyth, D.J.; Booth, S.L.; Jacques, P.F.; Burke, G.L.; Goodarzi, M.; Cheung, C.L.; Wolf, M.; Rice, K.; Goltzman, D.; Hidiroglou, N.; Ladouceur, M.; Wareham, N.J.; Hocking, L.J.; Hart, D.; Arden, N.K.; Cooper, C.; Malik, S.; Fraser, W.D.; Hartikainen, A.L.; Zhai, G.; Macdonald, H.M.; Forouhi, N.G.; Loos, R.J.; Reid, D.M.; Hakim, A.; Dennison, E.; Liu, Y.; Power, C.; Stevens, H.E.; Jaana, L.; Vasan, R.S.; Soranzo, N.; Bojunga, J.; Psaty, B.M.; Lorentzon, M.; Foroud, T.; Harris, T.B.; Hofman, A.; Jansson, J.O.; Cauley, J.A.; Uitterlinden, A.G.; Gibson, Q.; Järvelin, M.R.; Karasik, D.; Siscovick, D.S.; Econs, M.J.; Kritchevsky, S.B.; Florez, J.C.; Todd, J.A.; Dupuis, J.; Hyppönen, E.; Spector, T.D. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet, 2010, 376(9736), 180-188.
[http://dx.doi.org/10.1016/S0140-6736(10)60588-0] [PMID: 20541252]
]. DHCR7 gene encodes an enzyme that catalyses the last reaction in the cholesterol biosynthesis pathway using 7-DHC as a substrate. 7-DHC is a common precursor of vitamin D3 and cholesterol. Indeed, in the skin, 7-DHC can be converted into vitamin D3 by UVB radiations. The conversion of 7-DHC by DHCR7 removes the substrate (7-DHC) from the synthetic pathway of vitamin D3. The results from GWAS identified genetic variants in the DHCR-7 gene as strong determinants of circulating 25(OH)D levels [87Ahn, J; Yu, K; Stolzenberg-Solomon, R; Simon, KC; McCullough, ML; Gallicchio, L; Jacobs, EJ; Ascherio, A; Helzlsouer, K Hum. Mol, Genet., Genome-wide association study of circulating vitamin D levels, 2010, 19, 2739-45.
[http://dx.doi.org/10.1093/hmg/ddq155]
, 88Wang, T.J.; Zhang, F.; Richards, J.B.; Kestenbaum, B.; van Meurs, J.B.; Berry, D.; Kiel, D.P.; Streeten, E.A.; Ohlsson, C.; Koller, D.L.; Peltonen, L.; Cooper, J.D.; O’Reilly, P.F.; Houston, D.K.; Glazer, N.L.; Vandenput, L.; Peacock, M.; Shi, J.; Rivadeneira, F.; McCarthy, M.I.; Anneli, P.; de Boer, I.H.; Mangino, M.; Kato, B.; Smyth, D.J.; Booth, S.L.; Jacques, P.F.; Burke, G.L.; Goodarzi, M.; Cheung, C.L.; Wolf, M.; Rice, K.; Goltzman, D.; Hidiroglou, N.; Ladouceur, M.; Wareham, N.J.; Hocking, L.J.; Hart, D.; Arden, N.K.; Cooper, C.; Malik, S.; Fraser, W.D.; Hartikainen, A.L.; Zhai, G.; Macdonald, H.M.; Forouhi, N.G.; Loos, R.J.; Reid, D.M.; Hakim, A.; Dennison, E.; Liu, Y.; Power, C.; Stevens, H.E.; Jaana, L.; Vasan, R.S.; Soranzo, N.; Bojunga, J.; Psaty, B.M.; Lorentzon, M.; Foroud, T.; Harris, T.B.; Hofman, A.; Jansson, J.O.; Cauley, J.A.; Uitterlinden, A.G.; Gibson, Q.; Järvelin, M.R.; Karasik, D.; Siscovick, D.S.; Econs, M.J.; Kritchevsky, S.B.; Florez, J.C.; Todd, J.A.; Dupuis, J.; Hyppönen, E.; Spector, T.D. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet, 2010, 376(9736), 180-188.
[http://dx.doi.org/10.1016/S0140-6736(10)60588-0] [PMID: 20541252]
] and several evidence support this association [89Prabhu, A.V.; Luu, W.; Li, D.; Sharpe, L.J.; Brown, A.J. DHCR7: A vital enzyme switch between cholesterol and vitamin D production. Prog. Lipid Res., 2016, 64, 138-151.
[http://dx.doi.org/10.1016/j.plipres.2016.09.003] [PMID: 27697512]
-91Wassif, C.A.; Zhu, P.; Kratz, L.; Krakowiak, P.A.; Battaile, K.P.; Weight, F.F.; Grinberg, A.; Steiner, R.D.; Nwokoro, N.A.; Kelley, R.I.; Stewart, R.R.; Porter, F.D. Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith--Lemli--Opitz syndrome. Hum. Mol. Genet., 2001, 10(6), 555-564.
[http://dx.doi.org/10.1093/hmg/10.6.555] [PMID: 11230174]
]. However, only a few studies addressed the influence of allelic variation on this locus and MS [85Allan, G.M.; Cranston, L.; Lindblad, A.; McCormack, J.; Kolber, M.R.; Garrison, S.; Korownyk, C.; Vitamin, D. Vitamin D: A Narrative Review Examining the Evidence for Ten Beliefs. J. Gen. Intern. Med., 2016, 31(7), 780-791.
[http://dx.doi.org/10.1007/s11606-016-3645-y] [PMID: 26951286]
-88Wang, T.J.; Zhang, F.; Richards, J.B.; Kestenbaum, B.; van Meurs, J.B.; Berry, D.; Kiel, D.P.; Streeten, E.A.; Ohlsson, C.; Koller, D.L.; Peltonen, L.; Cooper, J.D.; O’Reilly, P.F.; Houston, D.K.; Glazer, N.L.; Vandenput, L.; Peacock, M.; Shi, J.; Rivadeneira, F.; McCarthy, M.I.; Anneli, P.; de Boer, I.H.; Mangino, M.; Kato, B.; Smyth, D.J.; Booth, S.L.; Jacques, P.F.; Burke, G.L.; Goodarzi, M.; Cheung, C.L.; Wolf, M.; Rice, K.; Goltzman, D.; Hidiroglou, N.; Ladouceur, M.; Wareham, N.J.; Hocking, L.J.; Hart, D.; Arden, N.K.; Cooper, C.; Malik, S.; Fraser, W.D.; Hartikainen, A.L.; Zhai, G.; Macdonald, H.M.; Forouhi, N.G.; Loos, R.J.; Reid, D.M.; Hakim, A.; Dennison, E.; Liu, Y.; Power, C.; Stevens, H.E.; Jaana, L.; Vasan, R.S.; Soranzo, N.; Bojunga, J.; Psaty, B.M.; Lorentzon, M.; Foroud, T.; Harris, T.B.; Hofman, A.; Jansson, J.O.; Cauley, J.A.; Uitterlinden, A.G.; Gibson, Q.; Järvelin, M.R.; Karasik, D.; Siscovick, D.S.; Econs, M.J.; Kritchevsky, S.B.; Florez, J.C.; Todd, J.A.; Dupuis, J.; Hyppönen, E.; Spector, T.D. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet, 2010, 376(9736), 180-188.
[http://dx.doi.org/10.1016/S0140-6736(10)60588-0] [PMID: 20541252]
], with contrasting results. The influence of DHCR7 on MS risk requires further investigations.

The first hepatic hydroxylation of vitamin D can be catalysed by CYP2R1, CYP27A1 and CYP3A4. Among these enzymes, CYP2R1 has a prominent role in vitamin D metabolism, while CYP27A1 and CYP3A4 are also involved in the hydroxylation of other substrates.

The association between CYP2R1 and hypovitaminosis D was first identified by GWAS [87Ahn, J; Yu, K; Stolzenberg-Solomon, R; Simon, KC; McCullough, ML; Gallicchio, L; Jacobs, EJ; Ascherio, A; Helzlsouer, K Hum. Mol, Genet., Genome-wide association study of circulating vitamin D levels, 2010, 19, 2739-45.
[http://dx.doi.org/10.1093/hmg/ddq155]
, 88Wang, T.J.; Zhang, F.; Richards, J.B.; Kestenbaum, B.; van Meurs, J.B.; Berry, D.; Kiel, D.P.; Streeten, E.A.; Ohlsson, C.; Koller, D.L.; Peltonen, L.; Cooper, J.D.; O’Reilly, P.F.; Houston, D.K.; Glazer, N.L.; Vandenput, L.; Peacock, M.; Shi, J.; Rivadeneira, F.; McCarthy, M.I.; Anneli, P.; de Boer, I.H.; Mangino, M.; Kato, B.; Smyth, D.J.; Booth, S.L.; Jacques, P.F.; Burke, G.L.; Goodarzi, M.; Cheung, C.L.; Wolf, M.; Rice, K.; Goltzman, D.; Hidiroglou, N.; Ladouceur, M.; Wareham, N.J.; Hocking, L.J.; Hart, D.; Arden, N.K.; Cooper, C.; Malik, S.; Fraser, W.D.; Hartikainen, A.L.; Zhai, G.; Macdonald, H.M.; Forouhi, N.G.; Loos, R.J.; Reid, D.M.; Hakim, A.; Dennison, E.; Liu, Y.; Power, C.; Stevens, H.E.; Jaana, L.; Vasan, R.S.; Soranzo, N.; Bojunga, J.; Psaty, B.M.; Lorentzon, M.; Foroud, T.; Harris, T.B.; Hofman, A.; Jansson, J.O.; Cauley, J.A.; Uitterlinden, A.G.; Gibson, Q.; Järvelin, M.R.; Karasik, D.; Siscovick, D.S.; Econs, M.J.; Kritchevsky, S.B.; Florez, J.C.; Todd, J.A.; Dupuis, J.; Hyppönen, E.; Spector, T.D. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet, 2010, 376(9736), 180-188.
[http://dx.doi.org/10.1016/S0140-6736(10)60588-0] [PMID: 20541252]
]. Based on this evidence, case-control studies were performed to investigate a possible link between CYP2R1 polymorphisms and MS risk [92Scazzone, C.; Agnello, L.; Ragonese, P.; Lo Sasso, B.; Bellia, C.; Bivona, G.; Schillaci, R.; Salemi, G.; Ciaccio, M. Association of CYP2R1 rs10766197 with MS risk and disease progression. J. Neurosci. Res., 2018, 96(2), 297-304.
[http://dx.doi.org/10.1002/jnr.24133] [PMID: 28834557]
-97Manousaki, D.; Dudding, T.; Haworth, S.; Hsu, Y.H.; Liu, C.T.; Medina-Gómez, C.; Voortman, T.; van der Velde, N.; Melhus, H.; Robinson-Cohen, C.; Cousminer, D.L.; Nethander, M.; Vandenput, L.; Noordam, R.; Forgetta, V.; Greenwood, C.M.T.; Biggs, M.L.; Psaty, B.M.; Rotter, J.I.; Zemel, B.S.; Mitchell, J.A.; Taylor, B.; Lorentzon, M.; Karlsson, M.; Jaddoe, V.V.W.; Tiemeier, H.; Campos-Obando, N.; Franco, O.H.; Utterlinden, A.G.; Broer, L.; van Schoor, N.M.; Ham, A.C.; Ikram, M.A.; Karasik, D.; de Mutsert, R.; Rosendaal, F.R.; den Heijer, M.; Wang, T.J.; Lind, L.; Orwoll, E.S.; Mook-Kanamori, D.O.; Michaëlsson, K.; Kestenbaum, B.; Ohlsson, C.; Mellström, D.; de Groot, L.C.P.G.M.; Grant, S.F.A.; Kiel, D.P.; Zillikens, M.C.; Rivadeneira, F.; Sawcer, S.; Timpson, N.J.; Richards, J.B. Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis. Am. J. Hum. Genet., 2017, 101(2), 227-238.
[http://dx.doi.org/10.1016/j.ajhg.2017.06.014] [PMID: 28757204]
], with encouraging results.

The second hydroxylation of vitamin D is catalysed by CYP27B1 in many cells and tissues [98Bikle, D.D. Extra Renal Synthesis of 1,25-dihydroxyvitamin D and its Health implications. Clin. Rev. Bone Miner. Metab., 2009, 7, 114-125.
[http://dx.doi.org/10.1007/s12018-009-9033-y]
].

The association between CYP27B1 and MS risk was first identified by a GWAS performed by the Australia and New Zealand Multiple Sclerosis Genetics (ANZgene) Consortium [99Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene). Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat. Genet., 2009, 41(7), 824-828.
[http://dx.doi.org/10.1038/ng.396] [PMID: 19525955]
]. Such association has been confirmed by some observational case-control and family studies [35Sawcer, S.; Hellenthal, G.; Pirinen, M.; Spencer, C.C.; Patsopoulos, N.A.; Moutsianas, L.; Dilthey, A.; Su, Z.; Freeman, C.; Hunt, S.E.; Edkins, S.; Gray, E.; Booth, D.R.; Potter, S.C.; Goris, A.; Band, G.; Oturai, A.B.; Strange, A.; Saarela, J.; Bellenguez, C.; Fontaine, B.; Gillman, M.; Hemmer, B.; Gwilliam, R.; Zipp, F.; Jayakumar, A.; Martin, R.; Leslie, S.; Hawkins, S.; Giannoulatou, E.; D’alfonso, S.; Blackburn, H.; Martinelli Boneschi, F.; Liddle, J.; Harbo, H.F.; Perez, M.L.; Spurkland, A.; Waller, M.J.; Mycko, M.P.; Ricketts, M.; Comabella, M.; Hammond, N.; Kockum, I.; McCann, O.T.; Ban, M.; Whittaker, P.; Kemppinen, A.; Weston, P.; Hawkins, C.; Widaa, S.; Zajicek, J.; Dronov, S.; Robertson, N.; Bumpstead, S.J.; Barcellos, L.F.; Ravindrarajah, R.; Abraham, R.; Alfredsson, L.; Ardlie, K.; Aubin, C.; Baker, A.; Baker, K.; Baranzini, S.E.; Bergamaschi, L.; Bergamaschi, R.; Bernstein, A.; Berthele, A.; Boggild, M.; Bradfield, J.P.; Brassat, D.; Broadley, S.A.; Buck, D.; Butzkueven, H.; Capra, R.; Carroll, W.M.; Cavalla, P.; Celius, E.G.; Cepok, S.; Chiavacci, R.; Clerget-Darpoux, F.; Clysters, K.; Comi, G.; Cossburn, M.; Cournu-Rebeix, I.; Cox, M.B.; Cozen, W.; Cree, B.A.; Cross, A.H.; Cusi, D.; Daly, M.J.; Davis, E.; de Bakker, P.I.; Debouverie, M.; D’hooghe, M.B.; Dixon, K.; Dobosi, R.; Dubois, B.; Ellinghaus, D.; Elovaara, I.; Esposito, F.; Fontenille, C.; Foote, S.; Franke, A.; Galimberti, D.; Ghezzi, A.; Glessner, J.; Gomez, R.; Gout, O.; Graham, C.; Grant, S.F.; Guerini, F.R.; Hakonarson, H.; Hall, P.; Hamsten, A.; Hartung, H.P.; Heard, R.N.; Heath, S.; Hobart, J.; Hoshi, M.; Infante-Duarte, C.; Ingram, G.; Ingram, W.; Islam, T.; Jagodic, M.; Kabesch, M.; Kermode, A.G.; Kilpatrick, T.J.; Kim, C.; Klopp, N.; Koivisto, K.; Larsson, M.; Lathrop, M.; Lechner-Scott, J.S.; Leone, M.A.; Leppä, V.; Liljedahl, U.; Bomfim, I.L.; Lincoln, R.R.; Link, J.; Liu, J.; Lorentzen, A.R.; Lupoli, S.; Macciardi, F.; Mack, T.; Marriott, M.; Martinelli, V.; Mason, D.; McCauley, J.L.; Mentch, F.; Mero, I.L.; Mihalova, T.; Montalban, X.; Mottershead, J.; Myhr, K.M.; Naldi, P.; Ollier, W.; Page, A.; Palotie, A.; Pelletier, J.; Piccio, L.; Pickersgill, T.; Piehl, F.; Pobywajlo, S.; Quach, H.L.; Ramsay, P.P.; Reunanen, M.; Reynolds, R.; Rioux, J.D.; Rodegher, M.; Roesner, S.; Rubio, J.P.; Rückert, I.M.; Salvetti, M.; Salvi, E.; Santaniello, A.; Schaefer, C.A.; Schreiber, S.; Schulze, C.; Scott, R.J.; Sellebjerg, F.; Selmaj, K.W.; Sexton, D.; Shen, L.; Simms-Acuna, B.; Skidmore, S.; Sleiman, P.M.; Smestad, C.; Sørensen, P.S.; Søndergaard, H.B.; Stankovich, J.; Strange, R.C.; Sulonen, A.M.; Sundqvist, E.; Syvänen, A.C.; Taddeo, F.; Taylor, B.; Blackwell, J.M.; Tienari, P.; Bramon, E.; Tourbah, A.; Brown, M.A.; Tronczynska, E.; Casas, J.P.; Tubridy, N.; Corvin, A.; Vickery, J.; Jankowski, J.; Villoslada, P.; Markus, H.S.; Wang, K.; Mathew, C.G.; Wason, J.; Palmer, C.N.; Wichmann, H.E.; Plomin, R.; Willoughby, E.; Rautanen, A.; Winkelmann, J.; Wittig, M.; Trembath, R.C.; Yaouanq, J.; Viswanathan, A.C.; Zhang, H.; Wood, N.W.; Zuvich, R.; Deloukas, P.; Langford, C.; Duncanson, A.; Oksenberg, J.R.; Pericak-Vance, M.A.; Haines, J.L.; Olsson, T.; Hillert, J.; Ivinson, A.J.; De Jager, P.L.; Peltonen, L.; Stewart, G.J.; Hafler, D.A.; Hauser, S.L.; McVean, G.; Donnelly, P.; Compston, A. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature, 2011, 476(7359), 214-219.
[http://dx.doi.org/10.1038/nature10251] [PMID: 21833088]
, 93Graves, J.S.; Barcellos, L.F.; Krupp, L.; Belman, A.; Shao, X.; Quach, H.; Hart, J.; Chitnis, T.; Weinstock-Guttman, B.; Aaen, G.; Benson, L.; Gorman, M.; Greenberg, B.; Lotze, T.; Soe, M.; Ness, J.; Rodriguez, M.; Rose, J.; Schreiner, T.; Tillema, J.M.; Waldman, A.; Casper, T.C.; Waubant, E. Vitamin D genes influence MS relapses in children. Mult. Scler., 2019, 13524585198458421352458519845842
[http://dx.doi.org/10.1177/1352458519845842] [PMID: 31081484]
, 96Simon, K.C.; Munger, K.L.; Xing Yang, ; Ascherio, A. Polymorphisms in vitamin D metabolism related genes and risk of multiple sclerosis. Mult. Scler., 2010, 16(2), 133-138.
[http://dx.doi.org/10.1177/1352458509355069] [PMID: 20007432]
, 100Sundqvist, E.; Bäärnhielm, M.; Alfredsson, L.; Hillert, J.; Olsson, T.; Kockum, I. Confirmation of association between multiple sclerosis and CYP27B1. Eur. J. Hum. Genet., 2010, 18(12), 1349-1352.
[http://dx.doi.org/10.1038/ejhg.2010.113] [PMID: 20648053]
-105Ban, M.; Caillier, S.; Mero, I.L.; Myhr, K.M.; Celius, E.G.; Aarseth, J.; Torkildsen, Ø.; Harbo, H.F.; Oksenberg, J.; Hauser, S.L.; Sawcer, S.; Compston, A. No evidence of association between mutant alleles of the CYP27B1 gene and multiple sclerosis. Ann. Neurol., 2013, 73(3), 430-432.
[http://dx.doi.org/10.1002/ana.23833] [PMID: 23444327]
].

The levels of both 25(OH)D and 1,25(OH)2D are tightly regulated by CYP24A1, which mediates a hydroxylation reaction at C-24 and C-23, producing inactive metabolites.

The transcriptional expression of CYP24A1 is regulated by 1,25(OH)2D through a negative feedback mechanism. Indeed, vitamin D induces mRNA expression by the interaction with two VDREs in the promoter region of CYP24A1.

Simon et al. first explored the association between SNPs in the CYP24A1 gene and MS risk in a nested case-control study, achieving inconsistent results. The role of CYP24A1 on MS genetic susceptibility was first detected by a GWAS [35Sawcer, S.; Hellenthal, G.; Pirinen, M.; Spencer, C.C.; Patsopoulos, N.A.; Moutsianas, L.; Dilthey, A.; Su, Z.; Freeman, C.; Hunt, S.E.; Edkins, S.; Gray, E.; Booth, D.R.; Potter, S.C.; Goris, A.; Band, G.; Oturai, A.B.; Strange, A.; Saarela, J.; Bellenguez, C.; Fontaine, B.; Gillman, M.; Hemmer, B.; Gwilliam, R.; Zipp, F.; Jayakumar, A.; Martin, R.; Leslie, S.; Hawkins, S.; Giannoulatou, E.; D’alfonso, S.; Blackburn, H.; Martinelli Boneschi, F.; Liddle, J.; Harbo, H.F.; Perez, M.L.; Spurkland, A.; Waller, M.J.; Mycko, M.P.; Ricketts, M.; Comabella, M.; Hammond, N.; Kockum, I.; McCann, O.T.; Ban, M.; Whittaker, P.; Kemppinen, A.; Weston, P.; Hawkins, C.; Widaa, S.; Zajicek, J.; Dronov, S.; Robertson, N.; Bumpstead, S.J.; Barcellos, L.F.; Ravindrarajah, R.; Abraham, R.; Alfredsson, L.; Ardlie, K.; Aubin, C.; Baker, A.; Baker, K.; Baranzini, S.E.; Bergamaschi, L.; Bergamaschi, R.; Bernstein, A.; Berthele, A.; Boggild, M.; Bradfield, J.P.; Brassat, D.; Broadley, S.A.; Buck, D.; Butzkueven, H.; Capra, R.; Carroll, W.M.; Cavalla, P.; Celius, E.G.; Cepok, S.; Chiavacci, R.; Clerget-Darpoux, F.; Clysters, K.; Comi, G.; Cossburn, M.; Cournu-Rebeix, I.; Cox, M.B.; Cozen, W.; Cree, B.A.; Cross, A.H.; Cusi, D.; Daly, M.J.; Davis, E.; de Bakker, P.I.; Debouverie, M.; D’hooghe, M.B.; Dixon, K.; Dobosi, R.; Dubois, B.; Ellinghaus, D.; Elovaara, I.; Esposito, F.; Fontenille, C.; Foote, S.; Franke, A.; Galimberti, D.; Ghezzi, A.; Glessner, J.; Gomez, R.; Gout, O.; Graham, C.; Grant, S.F.; Guerini, F.R.; Hakonarson, H.; Hall, P.; Hamsten, A.; Hartung, H.P.; Heard, R.N.; Heath, S.; Hobart, J.; Hoshi, M.; Infante-Duarte, C.; Ingram, G.; Ingram, W.; Islam, T.; Jagodic, M.; Kabesch, M.; Kermode, A.G.; Kilpatrick, T.J.; Kim, C.; Klopp, N.; Koivisto, K.; Larsson, M.; Lathrop, M.; Lechner-Scott, J.S.; Leone, M.A.; Leppä, V.; Liljedahl, U.; Bomfim, I.L.; Lincoln, R.R.; Link, J.; Liu, J.; Lorentzen, A.R.; Lupoli, S.; Macciardi, F.; Mack, T.; Marriott, M.; Martinelli, V.; Mason, D.; McCauley, J.L.; Mentch, F.; Mero, I.L.; Mihalova, T.; Montalban, X.; Mottershead, J.; Myhr, K.M.; Naldi, P.; Ollier, W.; Page, A.; Palotie, A.; Pelletier, J.; Piccio, L.; Pickersgill, T.; Piehl, F.; Pobywajlo, S.; Quach, H.L.; Ramsay, P.P.; Reunanen, M.; Reynolds, R.; Rioux, J.D.; Rodegher, M.; Roesner, S.; Rubio, J.P.; Rückert, I.M.; Salvetti, M.; Salvi, E.; Santaniello, A.; Schaefer, C.A.; Schreiber, S.; Schulze, C.; Scott, R.J.; Sellebjerg, F.; Selmaj, K.W.; Sexton, D.; Shen, L.; Simms-Acuna, B.; Skidmore, S.; Sleiman, P.M.; Smestad, C.; Sørensen, P.S.; Søndergaard, H.B.; Stankovich, J.; Strange, R.C.; Sulonen, A.M.; Sundqvist, E.; Syvänen, A.C.; Taddeo, F.; Taylor, B.; Blackwell, J.M.; Tienari, P.; Bramon, E.; Tourbah, A.; Brown, M.A.; Tronczynska, E.; Casas, J.P.; Tubridy, N.; Corvin, A.; Vickery, J.; Jankowski, J.; Villoslada, P.; Markus, H.S.; Wang, K.; Mathew, C.G.; Wason, J.; Palmer, C.N.; Wichmann, H.E.; Plomin, R.; Willoughby, E.; Rautanen, A.; Winkelmann, J.; Wittig, M.; Trembath, R.C.; Yaouanq, J.; Viswanathan, A.C.; Zhang, H.; Wood, N.W.; Zuvich, R.; Deloukas, P.; Langford, C.; Duncanson, A.; Oksenberg, J.R.; Pericak-Vance, M.A.; Haines, J.L.; Olsson, T.; Hillert, J.; Ivinson, A.J.; De Jager, P.L.; Peltonen, L.; Stewart, G.J.; Hafler, D.A.; Hauser, S.L.; McVean, G.; Donnelly, P.; Compston, A. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature, 2011, 476(7359), 214-219.
[http://dx.doi.org/10.1038/nature10251] [PMID: 21833088]
]. However, subsequent studies sometimes fail to replicate this finding [94Laursen, J.H.; Søndergaard, H.B.; Albrechtsen, A.; Frikke-Schmidt, R.; Koch-Henriksen, N.; Soelberg Sørensen, P.; Sellebjerg, F.; Oturai, A. Genetic and environmental determinants of 25-hydroxyvitamin D levels in multiple sclerosis. Mult. Scler., 2015, 21(11), 1414-1422.
[http://dx.doi.org/10.1177/1352458514563590] [PMID: 25533295]
, 102Zhuang, J.C.; Huang, Z.Y.; Zhao, G.X.; Yu, H.; Li, Z.X.; Wu, Z.Y. Variants of CYP27B1 are associated with both multiple sclerosis and neuromyelitis optica patients in Han Chinese population. Gene, 2015, 557(2), 236-239.
[http://dx.doi.org/10.1016/j.gene.2014.12.045] [PMID: 25542806]
, 106Orton, S.M.; Ramagopalan, S.V.; Para, A.E.; Lincoln, M.R.; Handunnetthi, L.; Chao, M.J.; Morahan, J.; Morrison, K.M.; Sadovnick, A.D.; Ebers, G.C. Vitamin D metabolic pathway genes and risk of multiple sclerosis in Canadians. J. Neurol. Sci., 2011, 305(1-2), 116-120.
[http://dx.doi.org/10.1016/j.jns.2011.02.032] [PMID: 21440908]
-108Lin, R.; Taylor, B.V.; Simpson, S., Jr; Charlesworth, J.; Ponsonby, A.L.; Pittas, F.; Dwyer, T.; van der Mei, I. Association between multiple sclerosis risk-associated SNPs and relapse and disability--a prospective cohort study. Mult. Scler., 2014, 20(3), 313-321.
[http://dx.doi.org/10.1177/1352458513496882] [PMID: 23886828]
]. Hence, the role of CYP24A1 polymorphisms in MS is still controversial.

Another protein with a key role in the vitamin D pathway is the VDBP, also known as Group-specific component (Gc), which regulates the vitamin D availability to target cells [109Gauzzi, M.C. Vitamin D-binding protein and multiple sclerosis: Evidence, controversies, and needs. Mult. Scler., 2018, 24(12), 1526-1535.
[http://dx.doi.org/10.1177/1352458518792433] [PMID: 30113253]
]. It belongs to the albumin gene family and it is synthetized in the liver and secreted in the blood where it binds most of the circulating vitamin D metabolites with high affinity (85-90%). VDBP also promotes the access of vitamin D to target cells through the interaction with transmembrane receptors, namely megalin and cubilin, which internalize the VDBP-vitamin D complex. VDBP also plays several other biological functions including scavenging action, fatty acid transport and macrophage activation [110Speeckaert, M.; Huang, G.; Delanghe, J.R.; Taes, Y.E. Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism. Clin. Chim. Acta, 2006, 372(1-2), 33-42.
[http://dx.doi.org/10.1016/j.cca.2006.03.011] [PMID: 16697362]
].

The GC gene, which codifies VDBP, is localized in chromosome 4 and extends over 35kb; it consists of 13 exons and 12 introns. GC is one of the most polymorphic genes of the whole genome [109Gauzzi, M.C. Vitamin D-binding protein and multiple sclerosis: Evidence, controversies, and needs. Mult. Scler., 2018, 24(12), 1526-1535.
[http://dx.doi.org/10.1177/1352458518792433] [PMID: 30113253]
]. Among all the polymorphisms identified in the GC gene, two non-synonymous SNPs in the exon 11, the rs7041 and the rs4588, have been widely investigated in MS due to their influence on the vitamin D status, achieving conflicting results [93Graves, J.S.; Barcellos, L.F.; Krupp, L.; Belman, A.; Shao, X.; Quach, H.; Hart, J.; Chitnis, T.; Weinstock-Guttman, B.; Aaen, G.; Benson, L.; Gorman, M.; Greenberg, B.; Lotze, T.; Soe, M.; Ness, J.; Rodriguez, M.; Rose, J.; Schreiner, T.; Tillema, J.M.; Waldman, A.; Casper, T.C.; Waubant, E. Vitamin D genes influence MS relapses in children. Mult. Scler., 2019, 13524585198458421352458519845842
[http://dx.doi.org/10.1177/1352458519845842] [PMID: 31081484]
-95Pytel, V.; Matías-Guiu, J.A.; Torre-Fuentes, L.; Montero-Escribano, P.; Maietta, P.; Botet, J.; Álvarez, S.; Gómez-Pinedo, U.; Matías-Guiu, J. 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., 2019, 9(4)e01272
[http://dx.doi.org/10.1002/brb3.1272] [PMID: 30900415]
, 106Orton, S.M.; Ramagopalan, S.V.; Para, A.E.; Lincoln, M.R.; Handunnetthi, L.; Chao, M.J.; Morahan, J.; Morrison, K.M.; Sadovnick, A.D.; Ebers, G.C. Vitamin D metabolic pathway genes and risk of multiple sclerosis in Canadians. J. Neurol. Sci., 2011, 305(1-2), 116-120.
[http://dx.doi.org/10.1016/j.jns.2011.02.032] [PMID: 21440908]
, 111Agnello, L.; Scazzone, C.; Lo Sasso, B.; Bellia, C.; Bivona, G.; Realmuto, S.; Brighina, F.; Schillaci, R.; Ragonese, P.; Salemi, G.; Ciaccio, M. VDBP, CYP27B1, and 25-Hydroxyvitamin D Gene Polymorphism Analyses in a Group of Sicilian Multiple Sclerosis Patients. Biochem. Genet., 2017, 55(2), 183-192.
[http://dx.doi.org/10.1007/s10528-016-9783-4] [PMID: 27904983]
-115Lindblom, B.; Wetterling, G.; Link, H. Distribution of group-specific component subtypes in multiple sclerosis. Acta Neurol. Scand., 1988, 78(5), 443-444.
[http://dx.doi.org/10.1111/j.1600-0404.1988.tb03683.x] [PMID: 3218452]
].

As above-mentioned, the genomic actions of vitamin D are mediated by VDR. It is a member of the nuclear receptor family of ligand-activated transcription factors, mainly localized in the cytoplasm. After binding 1,25(OH)2D, cytosolic VDR interacts with retinoid-X-receptor α (RXRα). The 1,25(OH)2D-VDR-RXRα complex moves into the nucleus where it regulates the expression of several genes through the interaction with VDRE in the promoter region of target genes [63Lu, M.; Taylor, B.V.; Körner, H. Genomic Effects of the Vitamin D Receptor: Potentially the Link between Vitamin D, Immune Cells, and Multiple Sclerosis. Front. Immunol., 2018, 9, 477.
[http://dx.doi.org/10.3389/fimmu.2018.00477] [PMID: 29593729]
, 116Jeon, S.M.; Shin, E.A. Exploring vitamin D metabolism and function in cancer. Exp. Mol. Med., 2018, 50(4), 20.
[http://dx.doi.org/10.1038/s12276-018-0038-9] [PMID: 29657326]
]. The following SNPs in the VDR gene have been widely investigated in MS: ApaI (rs7975232), BsmI (rs1544410), TaqI (rs731236), and FokI (rs2228570), achieving contrasting and contradictory results [96Simon, K.C.; Munger, K.L.; Xing Yang, ; Ascherio, A. Polymorphisms in vitamin D metabolism related genes and risk of multiple sclerosis. Mult. Scler., 2010, 16(2), 133-138.
[http://dx.doi.org/10.1177/1352458509355069] [PMID: 20007432]
, 117Bettencourt, A.; Boleixa, D.; Guimarães, A.L.; Leal, B.; Carvalho, C.; Brás, S.; Samões, R.; Santos, E.; Costa, P.P.; Silva, B.; da Silva, A.M. The vitamin D receptor gene FokI polymorphism and Multiple Sclerosis in a Northern Portuguese population. J. Neuroimmunol., 2017, 309, 34-37.
[http://dx.doi.org/10.1016/j.jneuroim.2017.05.005] [PMID: 28601283]
-141Křenek, P.; Benešová, Y.; Bienertová-Vašků, J.; Vašků, A. The Impact of Five VDR Polymorphisms on Multiple Sclerosis Risk and Progression: a Case-Control and Genotype-Phenotype Study. J. Mol. Neurosci., 2018, 64(4), 559-566.
[http://dx.doi.org/10.1007/s12031-018-1034-1] [PMID: 29589202]
]. While ApaI, BsmI and TaqI influence the VDR gene expression, FokI is associated with alterations of both protein structure and transcriptional activity of VDR (for a recent review of the association between VDR SNPs and the risk of MS see ref 142Zhang, Y.J.; Zhang, L.; Chen, S.Y.; Yang, G.J.; Huang, X.L.; Duan, Y.; Yang, L.J.; Ye, D.Q.; Wang, J. Association between VDR polymorphisms and multiple sclerosis: systematic review and updated meta-analysis of case-control studies. Neurol. Sci., 2018, 39(2), 225-234.
[http://dx.doi.org/10.1007/s10072-017-3175-3] [PMID: 29110148]
). While Tizaoui et al. reported an association of VDR polymorphisms with an increased risk of MS in large meta-analyses [143Tizaoui, 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, 243-52.
[http://dx.doi.org/10.1038/cmi.2014.47]
], Huang et al. [144Huang, J.; Xie, Z.F. Polymorphisms in the vitamin D receptor gene and multiple sclerosis risk: a meta-analysis of case-control studies. J. Neurol. Sci., 2012, 313(1-2), 79-85.
[http://dx.doi.org/10.1016/j.jns.2011.09.024] [PMID: 22029942]
] and Zhang et al. [142Zhang, Y.J.; Zhang, L.; Chen, S.Y.; Yang, G.J.; Huang, X.L.; Duan, Y.; Yang, L.J.; Ye, D.Q.; Wang, J. Association between VDR polymorphisms and multiple sclerosis: systematic review and updated meta-analysis of case-control studies. Neurol. Sci., 2018, 39(2), 225-234.
[http://dx.doi.org/10.1007/s10072-017-3175-3] [PMID: 29110148]
] conducted two meta-analyses showing opposite results. The reasons for this discrepancy could be the small sample size of most studies and, consequently, low statistical power, interactions with other genetic or environmental factors as well as clinical heterogeneity. Overall, the role of VDR genetic variations in MS risk must still be elucidated. The influence of RXR-α SNPs on MS risk has been evaluated in very few studies that found no association [95Pytel, V.; Matías-Guiu, J.A.; Torre-Fuentes, L.; Montero-Escribano, P.; Maietta, P.; Botet, J.; Álvarez, S.; Gómez-Pinedo, U.; Matías-Guiu, J. 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., 2019, 9(4)e01272
[http://dx.doi.org/10.1002/brb3.1272] [PMID: 30900415]
, 107Agnello, L.; Scazzone, C.; Lo Sasso, B.; Ragonese, P.; Milano, S.; Salemi, G.; Ciaccio, M. CYP27A1, CYP24A1, and RXR-α Polymorphisms, Vitamin D, and Multiple Sclerosis: a Pilot Study. J. Mol. Neurosci., 2018, 66(1), 77-84.
[http://dx.doi.org/10.1007/s12031-018-1152-9] [PMID: 30088172]
]

MARRS, the receptor that mediates the non-genomic actions of vitamin D, is expressed in caveolae-enriched plasma membranes of target cells [145Huhtakangas, J.A.; Olivera, C.J.; Bishop, J.E.; Zanello, L.P.; Norman, A.W. 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., 2004, 18(11), 2660-2671.
[http://dx.doi.org/10.1210/me.2004-0116] [PMID: 15272054]
, 146Hettinghouse, A.; Liu, R.; Liu, C.J. Multifunctional molecule ERp57: From cancer to neurodegenerative diseases. Pharmacol. Ther., 2018, 181, 34-48.
[http://dx.doi.org/10.1016/j.pharmthera.2017.07.011] [PMID: 28723413]
]. To date, only one study investigated the influence of SNPs in the gene codifying for MARRS on MS risk, achieving inconsistent results [95Pytel, V.; Matías-Guiu, J.A.; Torre-Fuentes, L.; Montero-Escribano, P.; Maietta, P.; Botet, J.; Álvarez, S.; Gómez-Pinedo, U.; Matías-Guiu, J. 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., 2019, 9(4)e01272
[http://dx.doi.org/10.1002/brb3.1272] [PMID: 30900415]
].

CONCLUSION

The role of hypovitaminosis D in MS risk has emerged in the last decades and is supported by robust literature evidence. Notably, genetic background influences vitamin D status. Thus, several authors investigated the relationship among MS, vitamin D status and SNPs in genes involved in the vitamin D pathway. However, contradictory findings have been observed. This could be due to study limitations, including heterogeneity in the study design and small sample size. Moreover, standardization of 25(OH)D measurement is still lacking, which hampers the development of consensus guidelines about vitamin D deficiency, insufficiency and sufficiency. Thus, literature data does not allow drawing conclusions on the association among vitamin D status, genetics and MS. Further studies are required to better understand the role of vitamin D- related gene variants in the risk and progression of MS.

LIST OF ABBREVIATIONS

CNS  = Central Nervous System;
UV  = Ultra Violet ;
SNPs  = Single Nucleotide Polymorphisms;
UVB  = Ultraviolet B;
25(OH)D  = 25-hydroxyl-vitamin-D;
1,25(OH)D  = 1,25-dihydroxy-vitamin-D;
VDR  = Vitamin D Receptor; MARRS, Rapid Response Steroid Binding Proteins;
CYPs  = Cytochrome P450 Enzymes;
GWAS  = Genome Wide Association Study;
OCB  = Oligoclonal Band;
EAE  = Experimental Autoimmune Encephal Omyelitis;
Th  = T Helper;
IFN-γ  = Interferon Gamma;
IL  = Interleukin;
GM-CSF  = Granulocite-Macrophage Colony-Stimulating Factor;
APC  = Antigen Presenting Cells;
CD-CV  = Common-Disease-Common Variant; T-regs, Regulatory T-cells;
OPC  = Oligodendrocyte Precursor Cells;
RCT  = Randomized Controlled Trials;
MR  = Mendelian Randomization;
VDREs  = Vitamin D Responsive Elements;
DHCR7  = 7-Dehydrocholesterol Reductase;
GC  = Group-Specific Component;
7-DHC  = 7-Dehydro-Cholesterol;
25,24(OH)2D2/3  = 25,24-Dihydroxy-Vitamin-D2/3;
1,25(OH)D-26,23lactione  = 1,25-Dihydroxy-Vitamin D-26,23lactione;
MARRS  = Membrane-Associated Rapid Response Steroid Binding Proteins.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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