Human Molecular Genetics Advance Access originally published online on June 20, 2007
Human Molecular Genetics 2007 16(16):1951-1958; doi:10.1093/hmg/ddm142
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Transmission of class I/II multi-locus MHC haplotypes and multiple sclerosis susceptibility: accounting for linkage disequilibrium
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 and 4 Division of Neurology, Department of Medical Genetics and Faculty of Medicine, University of British Columbia, Vancouver, Canada V6T 1Z4
* To whom correspondence should be addressed. Tel: +44 1865231903; Fax: +44 1865231914; Email: 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 transmission disequilibrium test 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 = 2.41 x 10–5) and -HLA-A*03 (P = 8.42 x 10–6) and several HLA-DRB1*15-HLA-B haplotypes including HLA-DRB1*15-HLA-B*07 (P = 2.23 x 10–10). 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 frequency of allelic associations not being replicated emphasizes the requirement for constructing multi-locus haplotypes in dissecting associations in regions of tight LD.
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