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Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

Original publication

DOI

10.1038/ng.3176

Type

Journal

Nat Genet

Publication Date

02/2015

Volume

47

Pages

172 - 179

Keywords

Alleles, Chromosome Mapping, Colitis, Ulcerative, Crohn Disease, Genetic Linkage, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Genotyping Techniques, HLA-DRB1 Chains, Heterozygote, Humans, Inflammatory Bowel Diseases, Major Histocompatibility Complex, Phenotype, Polymorphism, Single Nucleotide