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Human Molecular Genetics Advance Access originally published online on June 1, 2005
Human Molecular Genetics 2005 14(14):2019-2026; doi:10.1093/hmg/ddi206
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Complex interactions among MHC haplotypes in multiple sclerosis: susceptibility and resistance

David A. Dyment1, Blanca M. Herrera1, M. Zameel Cader1, Cristen J. Willer1, Matthew R. Lincoln1, A. Dessa Sadovnick2, Neil Risch3 and George C. Ebers1,*

1The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, 2Department of Medical Genetics and Faculty of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada and 3Department of Genetics, Stanford University, California, USA

* To whom correspondence should be addressed at: Department of Clinical Neurology, University of Oxford, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK. Tel: +44 1865287659; Fax: +44 1865287533; Email: george.ebers{at}clneuro.oxford.ac.uk

Received March 9, 2005; Revised May 13, 2005; Accepted May 24, 2005

Mechanisms for observed associations within the major histocompatibility complex (MHC) and autoimmune diseases including multiple sclerosis (MS) remain uncertain. Genotyping of the HLA Class II DRB1 locus in 4347 individuals from 873 multiplex families with MS highlights the genetic complexity of this locus. Excess allele sharing in sibling pair families lacking DRB1*15 and DRB1*17 (58.5% sharing; P=0.012) was comparable to that seen where parents were DRB1*15 positive (62%, P=0.0006). DRB1*17 (P=0.00027) was clearly established as an MS susceptibility allele in addition to DRB1*15 (P<10–14). DRB1*14 showed striking under-transmission (P=0.000032) to affected offspring newly establishing this allele as a broadly acting resistance factor. Trans interactions were seen in both DRB1*15 and non-DRB1*15 bearing genotype combinations. DRB1*08 was transmitted preferentially with DRB1*15 (P=0.0114) and, in the presence of DRB1*08, the transmission of DRB1*15 was almost invariable (37 transmissions to one non-transmission). DRB1*01 was under-transmitted to offspring in the presence of DRB1*15 (P=0.019). Both DRB1*01 and DRB1*14 haplotypes carry DQA1*01-DQB1*05 alleles, suggesting a common DQ-related mechanism for the protection mediated by these haplotypes. These studies demonstrate that it is the Class II genotype that determines susceptibility and resistance to MS. By analogy with celiac disease and type I diabetes, the pattern of susceptibility strongly supports an autoimmune aetiology.


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