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INVITED REVIEW

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Genetic polymorphisms related to vitamin D and the therapeutic potential of vitamin D in multiple sclerosis1 Masaaki Niino and Yusei Miyazaki

Abstract: Vitamin D receptors (VDRs), which are responsible for most vitamin D functions, are expressed on various immune cells. Vitamin D is considered to be a potent immunomodulator. A variety of cells in the central nervous system (CNS) also express VDRs; thus, vitamin D may play a role in the regulation of neurodegeneration and repair processes within the CNS. Considered together with epidemiological studies, low vitamin D status is reckoned to be one of the risk factors for multiple sclerosis (MS). Further, vitamin D is considered to be a possible treatment for MS. However, previous clinical trials with small cohorts have not demonstrated significant effects of vitamin D in MS. Current ongoing clinical trials with large cohorts could provide answers with respect to the clinical effects of vitamin D in MS. However, genetic studies have suggested that genes associated with vitamin D, including VDRs, are susceptible genes for MS. Vitamin D needs to be considered from the perspective of the interaction between vitamin-D-related genetic factors and environmental factors affecting vitamin D levels. Key words: genetics, cytokine, risk factor, vitamin D receptor, therapy. Résumé : Les récepteurs de la vitamine D, avec lesquels on associe la plupart de ses effets, sont exprimés a` la surface de diverses cellules immunitaires. De fait, on considère la vitamine D comme un puissant immunomodulateur. On sait qu’une variété de cellules du système nerveux central (SNC) expriment aussi les récepteurs de la vitamine D, et celle-ci pourrait donc jouer un rôle dans la régulation de la neurodégénérescence ainsi que dans les processus de réparation au sein du SNC. Avec des études épidémiologiques a` l’appui, on considère que la carence en vitamine D fait partie des facteurs de risque de la sclérose en plaques (SP) et même que l’administration de vitamine D pourrait faire office de traitement éventuel contre cette maladie. Cependant, des essais cliniques antérieurs menés auprès de petites cohortes de patients n’ont pas montré d’effet notable de la vitamine D dans le cadre du traitement de la SP. En revanche, des essais cliniques menés actuellement auprès de grandes cohortes de patients pourraient être en mesure de répondre a` certaines questions portant sur les effets cliniques de la vitamine D dans ce contexte. Par ailleurs, des études de génétiques ont permis de penser que les gènes relatifs a` la vitamine D, y compris ceux des récepteurs de la vitamine D, sont des gènes de susceptibilité pour la SP. Nous devons considérer la vitamine D sous l’angle des facteurs génétiques liés a` la vitamine D ainsi que sous celui des facteurs environnementaux qui influencent les taux de vitamine D. [Traduit par la Rédaction] Mots-clés : génétique, cytokine, facteur de risque, récepteur de la vitamine D, traitement.

Introduction Latitudinal differences in the prevalence of multiple sclerosis (MS) have suggested low vitamin D status as a risk factor for MS because exposure of the skin to the sun, particularly to ultraviolet (UV)-B light, is the primary source of vitamin D. Low vitamin D status is considered to be associated with the risk of MS (Munger et al. 2006; Salzer et al. 2012), disease activity (Soilu-Hänninen et al. 2008; Smolders et al. 2008; Mowry et al. 2010, 2012; Simpson et al. 2010; Løken-Amsrud et al. 2012; Runia et al. 2012; Ascherio et al. 2014), and severe disease prognosis (van der Mei et al. 2007; Smolders et al. 2008; Weinstock-Guttman et al. 2011; Ascherio et al. 2014). Various effects of vitamin D in the pathogenesis of MS have been considered, and one of the most critical functions is immunomodulation. Many types of immune cells express vitamin D receptors (VDRs), and various immune cell functions, such as proliferation and cytokine production, are affected by vitamin D. In an animal model of MS, vitamin D and its analogs were found to

suppress experimental autoimmune encephalomyelitis (EAE) (see review by Niino 2010). Vitamin D has great potential as a treatment for MS, and some clinical trials with large cohorts are ongoing. On the other hand, MS is considered to be a clinically heterogeneous condition with a complex etiology, in which environmental and genetic factors are implicated, and some genes associated with vitamin D are considered to be candidate genes for MS. Taken together, it is suggested that vitamin D affects the pathogenesis of MS by a mechanism involving gene–environmental interactions. In this review, the correlations between vitamin D and MS are discussed; in particular, the implications for genes associated with vitamin D, and the therapeutic potential of vitamin D for the treatment of MS.

Vitamin D in multiple sclerosis Vitamin D deficiency in association with environmental factors is considered to be a potential contributor to the development of MS. A large prospective study has demonstrated that the risk of MS decreased with increasing serum levels of 25-hydroxyvitamin D

Received 27 September 2014. Accepted 12 January 2015. M. Niino. Department of Clinical Research, Hokkaido Medical Center, Sapporo, Japan. Y. Miyazaki. Department of Clinical Research, Hokkaido Medical Center, Sapporo, Japan; Department of Neurology, Hokkaido Medical Center, Sapporo, Japan. Corresponding author: Masaaki Niino (e-mail: [email protected]). 1This Invited Review is part of a Special Issue entitled “Pharmacology of vitamins and beyond: Vitamin D.” Can. J. Physiol. Pharmacol. 93: 319–325 (2015) dx.doi.org/10.1139/cjpp-2014-0374

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Table 1. Possible biological effects of vitamin D in the pathogenesis of multiple sclerosis. Possible biological effects of vitamin D

Reference

Enhancement of regulatory T cell activity Inhibition of B cell differentiation Induction of expression/production of IL-4, IL-5, IL-10, and TGF␤ Decrease in Th17 cell frequency and suppression of IL-17 production Induction of expression of antimicrobial peptides Enhancement of dendritic cell apoptosis and macrophage phagocytosis Inhibition of dendritic cell maturation Suppression of expression/production of IL-1, IL-2, IL-6, IL-12, IL-23, IFN␥, and TNF␣ Induction of nerve growth factor expression Protection against oxidative damage Protection against neuronal cell death

Gorman et al. 2007 Chen et al. 2007 Boonstra et al. 2001; Mahon et al. 2003; Daniel et al. 2008 Daniel et al. 2008 Liu et al. 2007 Penna and Adorini 2000 Griffin et al. 2000; Penna and Adorini 2000; Piemonti et al. 2000 Mahon et al. 2003; Daniel et al. 2008

(25(OH)D) among Caucasians (Munger et al. 2006). Further, data have been reported in support of the association between high levels of 25(OH)D during the years preceding the onset of the disease, and a decreased risk of MS (Salzer et al. 2012). Serum levels of vitamin D differ among ethnicities. In fact, serum levels of 25(OH)D are substantially lower in African Americans than in Caucasians (Munger et al. 2006), and serum levels of 25(OH)D are significantly lower in Hispanics with MS than in Caucasians with MS (Amezcua et al. 2012). This suggests that the association between vitamin D status and risk of MS differs among ethnicities. In a study of an African-American population, the levels of 25(OH)D were lower in MS patients compared with the controls (Gelfand et al. 2011). Further, among reports from Middle Eastern and Asian populations, the same tendency was reported for populations from Iran (Shaygannejad et al. 2010) and India (Pandit et al. 2013), and in a Japanese population, patients with secondary progressive MS had significantly lower 25(OH)D levels compared with controls whose blood samples were drawn during the summer (Niino et al. 2013). Therefore, patients of the same ethnicity with MS have lower vitamin D status, although optimal levels of 25(OH)D and factors influencing 25(OH)D status seem to differ according to race and ethnicity. Low vitamin D levels have been discussed as risk factors for the activity and progression of MS, as well as for risk of the disease. A large prospective investigation demonstrated that low levels of 25(OH)D early in the course of the disease were a strong risk factor for long-term MS activity and progression (Ascherio et al. 2014). Additionally, a prospective population-based cohort study demonstrated that higher 25(OH)D levels were associated with a reduced probability of relapse (Simpson et al. 2010). Further, it was suggested that vitamin D metabolites such as 25(OH)D had a protective effect against disability and brain atrophy among MS patients (Weinstock-Guttman et al. 2011). There is a study on the association of vitamin D status with interferon (IFN)␤, one of diseasemodifying drugs for MS. A prospective cohort of MS patients living in southern Tasmania showed that IFN␤ treatment only had a protective effect against relapse among persons with higher levels of 25(OH)D, and the reduced risk of relapse associated with IFN␤ may be modified by a positive effect of IFN␤ on serum levels of 25(OH)D (Stewart et al. 2012). Many effective functions of vitamin D in the pathogenesis of MS can be speculated from basic studies (Table 1). Immunologically, vitamin D receptors are expressed on various immune cells, and vitamin D exerts various effects on immune cells, including T cells, macrophages, monocytes, dendritic cells, NK cells, and even in B cells, as has been discussed in a previous review (Niino 2010). Regarding the immunological functions of vitamin D that are related to MS, 1,25(OH)2D significantly suppresses proliferation of myelin basic protein (MBP) specific T cells and reduces the number of cells secreting interleukin (IL)-17, which is one of the key cytokines in the pathogenesis of MS (Correale et al. 2009). In a pooled study with samples from different clinical trials, supple-

Neveu et al. 1994 Shinpo et al. 2000 Shinpo et al. 2000; Taniura et al. 2006

mentation with a high-dose of vitamin D reduced T cell proliferation in MS patients (Burton et al. 2010). CYP27B1 (an enzyme that converts 25(OH)D to the active hormone 1,25(OH)2D) and vitamin D receptors are expressed on a variety of cells in the central nervous system, including neurons and glial cells. Additionally, vitamin D promotes neurite outgrowth, maturation, and differentiation. It also promotes the release of neurotrophins. Taken together, these effects of vitamin D suggest that it may play a role in the regulation of neurodegeneration and repair processes within the central nervous system (Smolders et al. 2011b).

Vitamin D related genetic associations in multiple sclerosis MS is a clinically heterogeneous condition with a complex etiology involving environmental and genetic factors (Niino et al. 2007). Given the association of vitamin D and MS, as discussed above, genes associated with vitamin D are critical susceptible genes for this condition, and the correlations between genetic associations of genes associated with vitamin D in MS and the immunological association of vitamin D in MS have been investigated. The VDR gene is encoded on chromosome 12q13-14 and contains over 100 kb, divided into 8 introns and 9 exons. There are over 30 polymorphisms within the VDR gene. Four single-nucleotide polymorphisms (SNPs) have been extensively investigated in MS, which are FokI (rs2228570; previously dbSNP ID rs10735810) in exon 2, ApaI (rs7975232) and BsmI (rs1544410) in the introns flanked by exons 8 and 9, and TaqI (rs731236) in functional exon 9. FokI is a nonsynonymous single nucleotide polymorphism (SNP) located in the translation start site. ApaI and BsmI do not affect the VDR protein structure, and TaqI is a synonymous variation in the ligand-binding domain of the VDR gene. Regarding the role of FokI SNPs in MS, a FokI polymorphism was associated with reduced risk of MS (Partridge et al. 2004) and with severity in Caucasians with MS who are from northern Europe (Mamutse et al. 2008), although no association of the FokI polymorphism with MS was found in subjects from the Netherlands (Smolders et al. 2009a) or from Tasmania (Dickinson et al. 2009). Recently, a study using a familybased approach with a large number of included subjects found that the VDR FokI variant resulted in distorted transmission to the affected offspring in HLA-DRB1*15-negative individuals (Orton et al. 2011). Previously, we reported associations between MS and 2 SNPs (ApaI and BsmI) in the VDR gene in a Japanese population (Fukazawa et al. 1999; Niino et al. 2000). Moreover, a ApaI polymorphism was also found to be associated with a Caucasian MS population in Australia (Tajouri et al. 2005). The above data suggest that the haplotype of these polymorphisms may influence susceptibility to MS. In contrast, no such associations with MS were reported in other populations (Simon et al. 2010; Sioka et al. 2011). Regarding the role of TaqI SNPs in MS, studies from Australia suggested an association of TaqI polymorphisms with the risk of Published by NRC Research Press

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Niino and Miyazaki

developing MS in Caucasians (Tajouri et al. 2005; Cox et al. 2012), although other studies reported no associations of TaqI polymorphisms with MS risk in Tasmania (Dickinson et al. 2009) or in Greece (Sioka et al. 2011). Data from a recent meta-analysis showed that none of these 4 polymorphisms was associated with MS risk (Huang and Xie 2012). Ethnic and geographic factors may contribute to this heterogeneity. Therefore, further studies are needed to discuss the influence of these VDR genes. The odds ratios (ORs) associated with the VDR susceptibility SNPs FokI (rs2228570) and TaqI (rs731236) vary markedly depending on the presence or absence of HLA-DRB1*1501 alleles (Cox et al. 2012), and ORs associated with the HLA-DRB1*15 risk allele were affected by the TaqI polymorphism (rs731236) (Agliardi et al. 2011). These data suggest that the functional mechanism linking VDRmediated signaling and HLA-DRB1*1501 expression may have implications for disease susceptibility (Handel and Ramagopalan 2012). In the association between HLA and VDR variants in MS, the combination of ApaI polymorphisms and the HLA-DRB1*15:01 haplotype confers susceptibility to MS in a Japanese population (Niino et al. 2000) and in a Spanish population (Irizar et al. 2012). There were some studies on the critical effects of vitamin D related genetic polymorphisms on vitamin D function and metabolism. It has been reported that the FokI polymorphism in the VDR gene affects immune cell behavior and nuclear factor (NF)-␬B- and nuclear factor of activated T cell (NFAT)-driven transcription, as well as IL-12p40 promoter-driven transcription in transfection experiments (van Etten et al. 2007). Several studies have also suggested that immune regulation can be affected by polymorphisms in VDR (Colin et al. 2000; van Etten et al. 2007; Orton et al. 2008; Smolders et al. 2009b; Ahn et al. 2009), CYP27B1 (Orton et al. 2008), and DBP (Ahn et al. 2010; Sinotte et al. 2009), which influence circulating levels of 25(OH)D and (or) 1,25(OH)2D. Vitamin D binding protein (DBP) is the major vitamin D carrier protein, and its metabolites are responsible for the transport of cholecalciferol to the liver, 25(OH)D to the kidneys, and 1,25(OH)2D to target organs (Disanto et al. 2011). The human DBP gene is located on the chromosome 4q12-q13 and contains 13 exons and 12 introns. Previous studies have not shown any associations between the DBP SNPs and susceptibility to or the risk of MS (Steckley et al. 2000; Niino et al. 2002; Simon et al. 2010, 2011; Orton et al. 2011), although some variants in DBP have been reported to be associated with serum levels of 25(OH)D (Ahn et al. 2009; Sinotte et al. 2009; Simon et al. 2011). Regarding the gene–environment interaction in MS risk, CYP27B1 has a considerable impact. Genetic mutations in CYP27B1 are suggested to affect circulating levels of 1,25(OH)2D (Kim et al. 2007; Alzahrani et al. 2010). A genome-wide association study with a large sample size from Australia and New Zealand identified rs703842 on chromosome 12, which lies 1.76 kb upstream of the CYP27B1 gene (cytochrome P450 family 27 subfamily B), as a risk-associated SNP in MS (Australia and New Zealand Multiple Sclerosis Genetics Consortium 2009). Subsequently, this finding was confirmed by a large Swedish study (Sundqvist et al. 2010). This same variant was also shown to affect circulating 25(OH)D levels in an MS twin study (Orton et al. 2008). Further, a study regarding rare variants in CYP27B1 suggested a causative role of this gene in MS (Ramagopalan et al. 2011). The twin study demonstrated that the correlation of 25(OH)D levels in monozygotic twins was more than 2-fold that in dizygotic twins, and significant associations of 2 CYP27B1 SNP variants with 25(OH)D levels were observed (Orton et al. 2008). Based on these findings, we can state that vitamin D levels are regulated by genetic variation in CYP27B1 and VDR, perhaps suggesting their importance in MS pathogenesis (Handunnetthi et al. 2010). Genetic factors or factors affecting the gene–environment interaction influence the trait. In the human genome, VDR influences the transcription rate of vitamin D responsive genes by binding to vitamin D response elements (VDREs) (Handunnetthi et al. 2010). The VDRE gene was

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highly conserved in HLA-DR15 haplotypes (no mutations in over 600 chromosomes) but not in some other HLA-DRB1 haplotypes, which suggests a selective pressure to maintain this response element in the HLA-DR15 haplotype (Hewer et al. 2013). A VDRE motif was identified in the proximal HLA-DRB1 promoter region. Additionally, vitamin D interacts specifically with HLA-DRB1*15, the strongest candidate gene for MS, to influence its expression (Ramagopalan et al. 2009). This suggests vitamin D supplementation might be harmful in at least some MS patients because the active form of vitamin D increases HLA-DRB*15 expression in vitro (Ramagopalan et al. 2009). A 5-year longitudinal MS cohort study demonstrated that vitamin D was strongly associated with the reduced development of contrast-enhancing lesions in those who were HLA-DRB1*15:01-negative, whereas the effect was less substantial in those who were positive for HLA-DRB1*15:01 (Mowry et al. 2012). These data suggest that vitamin D supplementation should be investigated in MS patients with and without HLA-DRB*15 separately. A Spanish study reported an association between the risk of MS and rs12785878, which is located near DHCR7 on chromosome 11q12 (Alloza et al. 2012). The DHCR7 gene encodes 7-dehydrocholesterol reductase, which converts 7-dehydrocholesterol to cholesterol, thereby reducing availability for vitamin D synthesis in the skin. As discussed above, some vitamin D-related genes have been intensively investigated to determine their correlation with MS risk. Genetic polymorphisms vary among the different ethnic groups, and there is a possibility that vitamin D related genetic associations with disease risks and clinical profiles of MS may be different among ethnicities.

Therapeutic potential of vitamin D in multiple sclerosis The therapeutic effects of vitamin D and its analogue on EAE have been investigated and have been discussed in our previous review paper (Niino 2010). Supplementation with vitamin D metabolites, particularly 1,25(OH)2D, suppresses EAE; further, synthetic structural analogs of 1,25(OH)2D or combination therapies of 1,25(OH)2D and immunosuppressive agents, such as cyclosporin A and rapamycin that were developed to avoid side effects including hypercalcemia and renal calcification, were demonstrated to have positive effects on EAE symptoms (reviewed in Niino 2010). Conversely, VDR-knockout mice developed EAE, which could not be prevented with 1,25(OH)2D (Meehan and DeLuca 2002). Such a result suggests that VDR is necessary for the beneficial effects of 1,25(OH)2D in EAE. There are some published clinical studies of vitamin D supplementation for MS. Additionally, clinical trials investigating only the immunological effects of vitamin D supplementation have also been reported. A pilot study with healthy individuals demonstrated that supplementation with 5000–10 000 IU/day vitamin D significantly increased serum levels of 25(OH)D, increased production of the antiinflammatory cytokine IL-10, and reduced the frequency of pathogenic Th17 cells (Allen et al. 2012). Most previous clinical trials with vitamin D that investigated the clinical effects included small numbers of subjects; the safety and tolerability of supplemental vitamin D was the main concern rather than clinical outcomes (Table 2). Some clinical trials included only a treatment arm without a placebo group. In those studies, clinical effects were compared with clinical data at baseline or prior to vitamin D treatment, and they focused on side effects rather than clinical and radiological effects (Wingerchuk et al. 2005; Kimball et al. 2007; Smolders et al. 2010). Regarding tolerability, high doses of cholecalciferol (as much as 280 000 IU/week) for 28 weeks were well-tolerated by MS patients (Kimball et al. 2007). A small clinical trial of supplementation with 20 000 IU/day vitamin D for 12 weeks demonstrated tolerability of high-dose vitamin D supplementation without side-effects, including hypercalcemia, or hypercalciuria (Smolders et al. 2010). The open-label, randomized, Published by NRC Research Press

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Table 2. Clinical trials with vitamin D (calcitriol, cholecalciferol, ergocalciferol) for the treatment of multiple sclerosis. Max. dose

Duration (weeks)

N (treatment/ control)

Design of trial

Calcitriol 2.5 ␮g/day

48

15 (15/0)

U

0.5 ␮g/day

52

50 (25/25)

DB, R, C

Cholecalciferol 280 000 IU/week

28

12 (12/0)

U

40 000 IU/daya

52

49 (25/24)

O, R, C

20 000 IU/day 300 000 IU/month

12 26

15 (15/0) 62 (28/34)

U DB, R, C

20 000 IU/week

96

68 (35/33)

DB, R, C

20 000 IU/week

Ergocalciferol 6000 IU twice daily + 1000 IU in the high-dose group vs. 1000 IU daily in the lowdose group

52

66 (34/32)

DB, R, C

26

23 (11; 12)b

DB, R, C

Clinical results

Reference

4 patients experienced clinical relapses; 4 patients worsened in EDSS No difference in effects on the EDSS score or relapse rates between 2 groups

Wingerchuk et al. 2005

53% decreased mean Gd+ lesions in MRI from baseline; no differences in relapse rates and disease progression between baseline and the end-of-study 41% decrease of annualized relapse rates in treatment group; more stable/improved EDSS in treatment group vs. controls Decreased fatigue (n = 8), relapse (n = 1) No difference in EDSS and Gd+ lesions between treated group and controls No difference in percentage change in bone mineral density between treated group and controls No difference in ARR, EDSS, MSFC components, grip strength, and fatigue between 2 groups A significantly lower number of Gd+ lesions in treated group vs. controls; a tendency to reduced disability accumulation and to improved timed tandem walk in treated group vs. controls

Kimball et al. 2007

A higher exit EDSS and a higher proportion exhibiting relapse in high-dose group vs. low-dose group; no difference in MRI-based outcome measures between the 2 groups

Stein et al. 2011

Shaygannejad et al. 2012

Burton et al. 2010

Smolders et al. 2010 Mosayebi et al. 2011 Steffensen et al. 2011

Kampman et al. 2012

Soilu-Hänninen et al. 2012

Note: EDSS; expanded disability status scale, ARR; annualized relapse rate, MSFC; multiple sclerosis functional composite; U, uncontrolled; DB, double blind; R, randomized; C, controlled; O, open labelled. aIn the control group; up to 4000 IU/day of cholecalciferol permitted if desired. b11 in the high-dose group/12 in the low-dose group.

controlled, dose-escalation 52-week trial with cholecalciferol showed that supplementation with a high-dose of vitamin D (as much as 280 000 IU/week) did not lead to significant adverse events, including hypercalcemia, despite a significant increase in 25(OH)D levels, and the evidence for immunomodulatory effects suggested the potential use of cholecalciferol as a treatment for MS (Burton et al. 2010; Kimball et al. 2011). Further, the first randomized, doubleblind, placebo-controlled trial with vitamin D as add-on therapy to IFN␤-1b administered subcutaneously every other day showed favorable clinical and radiological outcomes, although most data were not statistically significant, possibly because of the small number of patients included (Soilu-Hänninen et al. 2012). Conversely, the 96-week randomized controlled trial with weekly supplementation of 20 000 IU vitamin D3 (cholecalciferol) did not result in beneficial effects on the measured MS-related outcomes such as annualized relapse rate (ARR), expanded disability status scale (EDSS), multiple sclerosis functional composite (MSFC) components, or fatigue, although treatment increased serum levels of 25(OH)D (Steffensen et al. 2011; Kampman et al. 2012). In previous clinical trials, vitamin D formulations such as vitamin D3 (cholecalciferol), vitamin D2 (ergocalciferol), or 1,25(OH)2D (calcitriol) were used. The vitamin D formulation used in most clinical trials was cholecalciferol. However, there are 2 main types of vitamin D supplements available: ergocalciferol and cholecalciferol. Human beings cannot synthesize vitamin D2; instead, it is derived from plant sources. A double-blind randomized controlled trial with vitamin D2 reported no therapeutic advantage in relapsing–remitting MS (RRMS) for high-dose D2 over low-dose D2

supplementation (Stein et al. 2011). Clinical trials with calcitriol, the metabolically active form of vitamin D, have yielded positive clinical findings thus far (Wingerchuk et al. 2005; Shaygannejad et al. 2012). Vitamin D2 is less effective than vitamin D3 for increasing serum 25(OH)D levels, and calcitriol has higher potency and a narrower therapeutic window than vitamin D2 or D3, which suggests those vitamin D formulations cannot be directly compared (James et al. 2013). A recent meta-analysis of randomized controlled trials demonstrated no significant association between high-dose vitamin D treatment and the risk of MS relapse (James et al. 2013). However, the duration of those clinical trials was short, one year at most, except for one study. Safety and efficacy data of long-term treatment with high-dose vitamin D supplementation are lacking. MS patients usually take DMDs for long periods, and long-term efficacy and safety are a major concern. Further, the negative results of most clinical trials, apart from the fact that they had small sample sizes, are related to the possibility that beneficial effects of vitamin D might be masked by subgroups of non-responders. For example, vitamin D levels tend to be lower in MS patients but not in all MS patients. Effects of supplementation with vitamin D may differ because of a person’s vitamin D levels before supplementation started. Further, the effects of supplementation with vitamin D may or may not also differ based on positivity for HLA-DRB1*15, because it has been suggested that vitamin D could affect the expression of HLA-DRB1*15 (Ramagopalan et al. 2009). Published by NRC Research Press

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Concluding remarks A couple of key questions remain to be answered that link vitamin D and MS: (i) Does vitamin D prevent MS? (ii) Is vitamin D an effective treatment for MS (Munger and Ascherio 2011)? Regarding the first question, many previous observational studies have suggested higher vitamin D levels decrease the risk of MS. However, there have been few clues to provide an answer to the second question. Currently, clinical trials with large cohorts are ongoing, such as the phase II, multicenter, double-blind, randomized, placebocontrolled trial called as SOLAR (Supplementation of VigantOL oil versus placebo as Add-on in patients with relapsing–remitting MS receiving Rebif treatment for 96 weeks), which is designed to assess the efficacy of vitamin D as an adjunctive therapy to subcutaneous injection of IFN␤-1a in RRMS patients (Smolders et al. 2011a). The results of this study may provide insight into the second question. As for vitamin D, the gene–environmental interactions affect the pathogenesis of MS as discussed. Close attention to the interaction should be paid when considering vitamin D as an alternative treatment option for MS.

Disclosures None of the authors have a financial interest to disclose in relation to the publication of the contents of this article or have a relationship with any company with such financial interests.

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Published by NRC Research Press

Genetic polymorphisms related to vitamin D and the therapeutic potential of vitamin D in multiple sclerosis.

Vitamin D receptors (VDRs), which are responsible for most vitamin D functions, are expressed on various immune cells. Vitamin D is considered to be a...
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