High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis

Philippe Goyette, Gabrielle Boucher, Dermot Mallon, Eva Ellinghaus, Luke Jostins, Hailiang Huang, Stephan Ripke, Elena S Gusareva, Vito Annese, Stephen L Hauser, Jorge R Oksenberg, Ingo Thomsen, Stephen Leslie, Mark J Daly, Kristel Van Steen, Richard H Duerr, Jeffrey C Barrett, Dermot P B McGovern, L Philip Schumm, James A TraherneMary N Carrington, Vasilis Kosmoliaptsis, Tom H Karlsen, Andre Franke, John D Rioux, International Inflammatory Bowel Disease Genetics Consortium, Paul Henderson

Research output: Contribution to journalArticlepeer-review

Abstract

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 languageEnglish
Pages (from-to)172-9
Number of pages8
JournalNature Genetics
Volume47
Issue number2
DOIs
Publication statusPublished - Feb 2015

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

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