Genetic susceptibility to multiple sclerosis is associated with genes of the major histocompatibility complex (MHC), particularly HLA-DRB1 and HLA-DQB1 (ref. 1). Both locus and allelic heterogeneity have been reported in this genomic region2,3. To clarify whether HLA-DRB1 itself, nearby genes in the region encoding the MHC or combinations of these loci underlie susceptibility to multiple sclerosis, we genotyped 1,185 Canadian and Finnish families with multiple sclerosis (n = 4,203 individuals) with a high-density SNP panel spanning the genes encoding the MHC and flanking genomic regions. Strong associations in Canadian and Finnish samples were observed with blocks in the HLA class II genomic region (P < 4.9 × 10−13 and P < 2.0 × 10−16, respectively), but the strongest association was with HLA-DRB1 (P < 4.4 × 10−17). Conditioning on either HLA-DRB1 or the most significant HLA class II haplotype block found no additional block or SNP association independent of the HLA class II genomic region. This study therefore indicates that MHC-associated susceptibility to multiple sclerosis is determined by HLA class II alleles, their interactions and closely neighboring variants.
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We thank S. Roumy, J.-F. Olivier and A. Verner for their assistance in large-scale genotyping; M. Leboeuf and P. Laflamme for informatics support; L.R. Cardon and A.P. Morris for statistical advice; the families with multiple sclerosis for their participation; members of the Canadian Collaborative Study Group, M.-L. Sumelahti, J. Wikström, I. Elovaara, K. Koivisto, T. Pirttilä and M. Reunanen for collecting samples from individuals with multiple sclerosis; D. Bronnikov for assistance with data collection; and K. Morrison, H. Armstrong, B. Scott, G.C. DeLuca, B.M. Herrera, S.-M. Orton, S. Ramagopalan and M. Chao for assistance with sample preparation. M.R.L. is supported by a research studentship from the Multiple Sclerosis Society of Canada and a Clarendon Scholarship from the University of Oxford. A.M. has received a fellowship from the Canadian Institutes of Health Research. T.J.H. is the recipient of a Clinician-Scientist Award in Translational Research by the Burroughs Wellcome Fund and an Investigator Award from the Canadian Institutes of Health Research. This work was supported by the MS Society of Canada Research Foundation, Genome Canada, Genome Quebec, the Helsinki University Central Hospital Research Foundation and the US National Institutes of Health and by a grant from the National MS Society (for L.P.).
The authors declare no competing financial interests.
LD structure of the extended MHC region in 3 Caucasian populations. (PDF 38490 kb)
SNP Coverage of the extended MHC region. (PDF 323 kb)
Haplotype block analysis. (PDF 13 kb)
Canadian and Finnish families by type. (PDF 6 kb)
Statistics for SNPs genotyped in this study. (PDF 55 kb)
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Lincoln, M., Montpetit, A., Cader, M. et al. A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis. Nat Genet 37, 1108–1112 (2005). https://doi.org/10.1038/ng1647
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