Journal Article

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

Michael J. Chao, Martin C.N.M. Barnardo, Guang-zhi Lui, Matthew R. Lincoln, Sreeram V. Ramagopalan, Blanca M. Herrera, David A. Dyment, A. Dessa Sadovnick and George C. Ebers

in Human Molecular Genetics

Volume 16, issue 16, pages 1951-1958
Published in print August 2007 | ISSN: 0964-6906
Published online June 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm142
Transmission of class I/II multi-locus MHC haplotypes and multiple sclerosis susceptibility: accounting for linkage disequilibrium

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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 × 10−5) and -HLA-A*03 (P = 8.42 × 10−6) and several HLA-DRB1*15-HLA-B haplotypes including HLA-DRB1*15-HLA-B*07 (P = 2.23 × 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.

Journal Article.  5561 words. 

Subjects: Genetics and Genomics

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