Advertisement
Research Article

Expression of the Multiple Sclerosis-Associated MHC Class II Allele HLA-DRB1*1501 Is Regulated by Vitamin D

  • Sreeram V. Ramagopalan equal contributor,

    equal contributor Contributed equally to this work with: Sreeram V. Ramagopalan, Narelle J. Maugeri

    Affiliations: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

    X
  • Narelle J. Maugeri equal contributor,

    equal contributor Contributed equally to this work with: Sreeram V. Ramagopalan, Narelle J. Maugeri

    Affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom

    X
  • Lahiru Handunnetthi,

    Affiliations: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

    X
  • Matthew R. Lincoln,

    Affiliations: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

    X
  • Sarah-Michelle Orton,

    Affiliations: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

    X
  • David A. Dyment,

    Affiliations: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

    X
  • Gabriele C. DeLuca,

    Affiliations: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

    X
  • Blanca M. Herrera,

    Affiliations: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

    X
  • Michael J. Chao,

    Affiliations: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

    X
  • A. Dessa Sadovnick,

    Affiliations: Department of Medical Genetics, Division of Neurology, University of British Columbia, UBC Hospital, Vancouver, British Columbia, Canada, Faculty of Medicine, Division of Neurology, University of British Columbia, UBC Hospital, Vancouver, British Columbia, Canada

    X
  • George C. Ebers mail,

    george.ebers@clneuro.ox.ac.uk (GCE); julian@well.ox.ac.uk (JCK)

    Affiliations: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

    X
  • Julian C. Knight mail

    george.ebers@clneuro.ox.ac.uk (GCE); julian@well.ox.ac.uk (JCK)

    Affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom

    X
  • Published: February 06, 2009
  • DOI: 10.1371/journal.pgen.1000369

Reader Comments (6)

Post a new comment on this article

Response to recent comments

Posted by Tbinder on 17 Oct 2009 at 09:19 GMT

Thank you for the responses to our comment about the VDRE sequence motif in the HLA-DRB1(*1501) gene and the possible role in the etiology of multiple sclerosis (MS). We find the link that Ramagopalan and colleagues show between the clearest genetic risk factor, i.e. DRB1*1501, on one side and a well-described environmental risk factor, i.e. low vitamin-D3 level, both intriguing and very interesting. We also agree with most of the comments to our letter. The main point that we wanted to convey is that the very same VDRE sequence motif that Ramagopalan et al. found via sequencing of a large sample of chromosomes from DRB1*1501 homozygotes, according to the IMGT database, also exists in individuals with numerous other HLA-DRB1 alleles that are not associated with MS. Therefore, the title of the article and sentences like: “Sequencing of this promoter in more than 1,000 chromosomes from HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*1501 haplotypes. In contrast, there was striking variation among non–MS-associated haplotypes.”, overemphasize the relation between the VDRE sequence motif, DRB1*1501 and MS. Even though most DRB1* alleles carry the VDRE sequence motif, the link between vitamin D, DRB1*1501 and MS remains in principle very interesting, but further investigation is clearly needed to confirm a functional interaction between vitamin D levels and the expression of MS-associated HLA-DR alleles.

Thomas M. C. Binder 1,§, Claudia Schubert 1, Thomas H. Eiermann 1 & Roland Martin 2

1 HLA Laboratory
Department of Transfusion Medicine
Diagnostic Center
University Medical Center Hamburg-Eppendorf
Martinistr. 52
D-20251 Hamburg, Germany
§ binder@uke.uni-hamburg.de

2 Center for Molecular Neurobiology
Institute for Neuroimmunology and Clinical MS Research (inims)
Falkenried 94
D-20251 Hamburg, Germany


Literature

Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Orton S-M, et al. 2009 Expression of the Multiple Sclerosis-Associated MHC Class II Allele HLA-DRB1*1501 Is Regulated by Vitamin D. PLoS Genetics 5(2): e1000369. doi:10.1371/journal.pgen.1000369

No competing interests declared.

RE: Response to recent comments

Gebers replied to Tbinder on 17 Oct 2009 at 20:46 GMT

We thank TBinder for his comments and opinions. We based our statements on sequencing a rather large number of haplotypes. We are sure that the opinions of TBinder would be of more interest if he too provided some data which would extend what we have already published and put in our last reply to his previous commentary.

TBinder appears to be relying on public database material which often relies on relatively few individuals from individual haplotypes. These can be heterogeneous despite matching for prominent disease-associated alleles.

However assays have been developed by ourselves and collaborators which have enabled large scale throughput for taking this forward which will clarify the population genetics of this regulatory sequence.

Prof GC Ebers
University of Oxford

No competing interests declared.