A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis

Matthew R Lincoln^1, 2, 10, Alexandre Montpetit^3, 4, 10, M Zameel Cader^1, 2, Janna Saarela⁵, David A Dyment^1, 2, Milvi Tiislar³, Vincent Ferretti³, Pentti J Tienari⁶, A Dessa Sadovnick⁷, Leena Peltonen^5, 8, 9, George C Ebers^1, 2 & Thomas J Hudson^3, 4

¹  Department of Clinical Neurology, Radcliffe Infirmary, University of Oxford, Oxford OX2 6HE, UK.

²  Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

³  McGill University and Genome Quebec Innovation Centre, Montreal, Quebec H3A 1A4, Canada.

⁴  Departments of Medicine and Human Genetics, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec H3G 1A4, Canada.

⁵  Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland.

⁶  Department of Neurology, University of Helsinki, Neuroscience Programme, Biomedicum-Helsinki, Haartmaninkatu 8, PL700, Helsinki, Finland.

⁷  Department of Medical Genetics and Faculty of Medicine (Division of Neurology), University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.

⁸  Department of Human Genetics, University of California, Los Angeles, Los Angeles, California, USA.

⁹  Department of Medical Genetics, University of Helsinki, Finland.

¹⁰  These authors contributed equally to this work.

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 region^{2, 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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