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Research Letters |

Vitamin D–Dependent Rickets, HLA-DRB1, and the Risk of Multiple Sclerosis FREE

Sreeram V. Ramagopalan, MA, DPhil; Heather E. C. Hanwell, MS; Gavin Giovannoni, MD, FRCP; Per Morten Knappskog, PhD; Harald I. Nyland, MD, PhD; Kjell-Morten Myhr, MD, PhD; George C. Ebers, MD, FRCP, FRCPC, FMedSci; Øivind Torkildsen, MD, PhD
[+] Author Affiliations

Author Affiliations: Wellcome Trust Centre for Human Genetics and Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford, England (Drs Ramagopalan and Ebers); Blizard Institute of Cell and Molecular Science, Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London, England (Drs Ramagopalan and Giovannoni); Departments of Nutritional Sciences and Neurosciences and Mental Health, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada (Ms Hanwell); Department of Clinical Medicine, University of Bergen, Bergen, Norway (Drs Knappskog, Nyland, Myhr, and Torkildsen); Center of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway (Dr Knappskog); and the Department of Neurology, Norwegian Multiple Sclerosis Competence Center, Haukeland University Hospital, Bergen, Norway (Drs Nyland, Myhr, and Torkildsen).


Arch Neurol. 2010;67(8):1034-1035. doi:10.1001/archneurol.2010.182.
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Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system characterized by myelin loss, axonal pathology, and eventual progressive neurological dysfunction.1 The cause of MS is not yet conclusively known; however, it is clear that genetic and environmental components are important.1 Genes play important roles in MS, with extended major histocompatibility complex haplotypes, especially those containing HLA-DRB1*15, exerting the strongest effect.1 The involvement of the environment is also inescapable, and the geographical distribution of MS suggests that low sunlight—and thus impaired vitamin D production—may be a key environmental risk factor for the disease.1 Evidence to support a role for vitamin D in MS comes from a number of studies including investigations that showed that vitamin D deficiency increases the risk of MS.2 Furthermore, vitamin D–dependent rickets type I (VDDR I, also known as pseudovitamin D deficiency rickets; OMIM 264700) has recently been described as an MS risk factor,3 Three Norwegian patients diagnosed in childhood with VDDR I rickets caused by mutations in the CYP27B1 (OMIM 609506) gene were later diagnosed with MS.3CYP27B1 encodes 25-hydroxyvitamin D-1α-hydroxylase, the enzyme that produces active vitamin D (calcitriol).

Recent evidence has highlighted the pleiotropic actions of calcitriol on immune and central nervous system development and function.4 The recently identified and functionally active vitamin D response element in the HLA-DRB1 promoter region suggests direct interactions between HLA-DRB1, the main susceptibility locus, and vitamin D, a strong candidate for mediating the environmental effect in MS etiology.5 Here we sought to obtain human leukocyte antigen (HLA) profiles of the Norwegian patients to see if vitamin D–HLA interactions might contribute to MS development in individuals with VDDR I.

After approval by the institutional ethics committees, blood samples were collected from the patients for genomic DNA extraction. HLA-DRB1 genotyping and sequencing has been previously described.5

All 3 patients carried the MS risk allele HLA-DRB1*15, with the previously described vitamin D response element present in the promoter.5 Patients 1 and 2 (as coded previously3) were homozygous for HLA-DRB1*15.

Vitamin D–HLA interactions are further strongly suggested to be important in the development of MS. Given that the frequency of VDDR I in the general population is very low, chance comorbidity of MS and VDDR I is unlikely but further studies to assess this are warranted. The high frequency of vitamin D insufficiency in the general population has led experts to consider vitamin D supplementation as a measure to reduce the prevalence of MS.1 However, the time period when supplementation would be most effective is still under debate.1 All 3 patients had exceptionally impaired vitamin D status prior to their VDDR I diagnosis, suggesting that impaired vitamin D status may exert its influence on MS susceptibility during very early childhood or the intrauterine period. This is in line with the recent finding of HLA-DRB1 underlying the month-of-birth effect in patients with MS,6 maternal effects in the disease,1 and place of birth influencing MS risk.1

Two patients were treated with 30 000 IU of ergocalciferol per day (AFI-D2 Forte; Nycomed Pharma, Zurich, Switzerland), and 1 patient received 0.25 μg of calcitriol per day (Rocaltrol; Roche, Basel Switzerland). The efficacy of ergocalciferol therapy in VDDR I, however, is challenged by the impaired or ablated conversion of vitamin D to calcitriol. As such, the ergocalciferol regimen may have failed to elevate circulating calcitriol to within the reference range. Vitamin D signaling was thus not optimized in the patients treated with ergocalciferol, raising the possibility that impaired vitamin D status could influence MS risk at later time periods. The incidence of MS is on the rise, and it seems increasingly probable that vitamin D is a major risk factor in many but not all countries. Studies of disease prevention seem timely.

ARTICLE INFORMATION

Correspondence: Professor G. C. Ebers, University Department of Clinical Neurology, Level 3, West Wing, The John Radcliffe Hospital, Oxford OX3 9DU, England (george.ebers@clneuro.ox.ac.uk).

Author Contributions: Dr Ramagopalan and Ms Hanwell contributed equally to the manuscript. Study concept and design: Ramagopalan, Ebers, and Torkildsen. Acquisition of data: Ramagopalan, Knappskog, Nyland, Myhr, Ebers, and Torkildsen. Analysis and interpretation of data: Ramagopalan, Hanwell, Giovannoni, and Ebers. Drafting of the manuscript: Ramagopalan, Hanwell, and Ebers. Critical revision of the manuscript for important intellectual content: Ramagopalan, Hanwell, Giovannoni, Knappskog, Nyland, Myhr, Ebers, and Torkildsen. Obtained funding: Myhr and Ebers. Administrative, technical, and material support: Giovannoni, Knappskog, Myhr, Ebers, and Torkildsen. Study supervision: Giovannoni, Nyland, Ebers, and Torkildsen.

Financial Disclosure: None reported.

Funding/Support: This study was supported by grants from the Multiple Sclerosis Society of Canada Scientific Research Foundation, the UK Multiple Sclerosis Society, the Bergen and Hordaland Multiple Sclerosis Society, the Odd Fellow, the Norwegian MS Society, and Kjell Alme's Legacy for Research in MS.

Ebers  GC Environmental factors and multiple sclerosis. Lancet Neurol 2008;7 (3) 268- 277
PubMed Link to Article
Munger  KLLevin  LIHollis  BWHoward  NSAscherio  A Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006;296 (23) 2832- 2838
PubMed Link to Article
Torkildsen  ØKnappskog  PMNyland  HIMyhr  KM Vitamin D–dependent rickets as a possible risk factor for multiple sclerosis. Arch Neurol 2008;65 (6) 809- 811
PubMed Link to Article
Smolders  JDamoiseaux  JMenheere  PHupperts  R Vitamin D as an immune modulator in multiple sclerosis, a review [published online ahead of print January 4, 2008]. J Neuroimmunol 2008;194 (1-2) 7- 17
PubMed Link to Article
Ramagopalan  SVMaugeri  NJHandunnetthi  L  et al.  Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet 2009;5 (2) e1000369
PubMed Link to Article
Ramagopalan  SVLink  JByrnes  JK  et al.  HLA-DRB1 and month of birth in multiple sclerosis. Neurology 2009;73 (24) 2107- 2111
PubMed Link to Article

Figures

Tables

References

Ebers  GC Environmental factors and multiple sclerosis. Lancet Neurol 2008;7 (3) 268- 277
PubMed Link to Article
Munger  KLLevin  LIHollis  BWHoward  NSAscherio  A Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006;296 (23) 2832- 2838
PubMed Link to Article
Torkildsen  ØKnappskog  PMNyland  HIMyhr  KM Vitamin D–dependent rickets as a possible risk factor for multiple sclerosis. Arch Neurol 2008;65 (6) 809- 811
PubMed Link to Article
Smolders  JDamoiseaux  JMenheere  PHupperts  R Vitamin D as an immune modulator in multiple sclerosis, a review [published online ahead of print January 4, 2008]. J Neuroimmunol 2008;194 (1-2) 7- 17
PubMed Link to Article
Ramagopalan  SVMaugeri  NJHandunnetthi  L  et al.  Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet 2009;5 (2) e1000369
PubMed Link to Article
Ramagopalan  SVLink  JByrnes  JK  et al.  HLA-DRB1 and month of birth in multiple sclerosis. Neurology 2009;73 (24) 2107- 2111
PubMed Link to Article

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