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Human Molecular Genetics Advance Access published online on June 20, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm142
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Transmission of class I/II multi-locus MHC haplotypes and multiple sclerosis susceptibility: accounting for linkage disequilibrium

Michael J. Chao1,2, Martin C. N. M. Barnardo3, Guang-zhi Bu1,2, Matthew R. Lincoln1,2, Sreeram V. Ramagopalan1,2, Blanca M. Herrera1,2, David A. Dyment1,2, A. Dessa Sadovnick4 and George C. Ebers1,2,*

1 Department of Clinical Neurology, University of Oxford, Level 3, West Wing, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK 2 Welcomes Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK 3 Oxford Transplant Centre, Nuffield Department of Surgery, Churchill Hospital, Oxford, OX3 7LJ, UK 4 Department of Medical Genetics and Faculty of Medicine, Division of Neurology, University of British Columbia, Vancouver, V6T 1Z4, Canada

* To whom correspondence should be addressed: Professor George C. Ebers, Department of Clinical Neurology, University of Oxford, Level 3 West Wing, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK, Telephone: (+44) 1865 231903, Fax: (+44) 1865 231914, E-mail: george.ebers{at}clneuro.ox.ac.uk

Received December 19, 2006; Revised April 10, 2007; Accepted May 31, 2007

The human major histocompatibility complex (MHC) class II region is associated with genetic susceptibility to multiple sclerosis (MS). Roles for HLA class I loci have been supported in several case-control studies, but this methodology does not consider the known linkage disequilibrium (LD) between class I and II loci. In 1258 individuals from 294 MS families we analysed class I and II interactions. Using TDT and haplotype analyses, we found positive associations between MS and several HLA-DRB1*15–HLA-A haplotypes including HLA-DRB1*15–HLA-A*02 (P = 2.41x10–05) and –HLA-A*03 (P = 8.42x10–06), and several HLA-DRB1*15–HLA-B haplotypes including HLA-DRB1*15–HLA-B*07 (P = 2.23x10–10).

HLA-DRB1*15 haplotypes divergent for reported HLA-A allelic associations were equally over-transmitted, illustrating no detectable effect of HLA-A or –B alleles in cis on susceptibility. HLA-A and –B alleles on haplotypes not bearing HLA-DRB1*15 were not over-transmitted. Similarly, general over-transmission of HLA-DRB1*15 haplotypes was independent of the HLA-B allele present. Furthermore, HLA-B*07 haplotypes from HLA-DRB1*X–HLA-B*X/HLA-DRB1*X–HLA-B*07 heterozygous parents were transmitted per random expectation giving no indication of HLA-B independence or trans complementation of HLA-DRB1*15 by HLA-DRB1*X–HLA-B*07 haplotypes. These results imply that many reports of class I allelic associations in MS are class II dependent, secondary to LD with class II loci. The lack of independent class I associations suggests that virus-related class I-antigen complexes are not T-cell targets in MS. The inability to replicate confirmed case-control associations highlights the importance of family-based analyses. The high frequency that allelic associations cannot be replicated emphasises the requirement for constructing multi-locus haplotypes in dissecting associations in regions of tight LD as illustrated by these results.


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