title: 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.
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.
authors.affiliation: Research Center, Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Goyette
authors.affiliation: Research Center, Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Boucher
authors.affiliation: 1] Department of Surgery, University of Cambridge, Cambridge, UK. [2] National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK.
authors.forename: Dermot
authors.identifier: 0000000174341201
authors.initials: D
authors.lastname: Mallon
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany.
authors.forename: Eva
authors.identifier: 0000000329143382
authors.initials: E
authors.lastname: Ellinghaus
authors.affiliation: 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK. [2] Christ Church, University of Oxford, St Aldates, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Jostins
authors.affiliation: 1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Hailiang
authors.identifier: 0000000314615762
authors.initials: H
authors.lastname: Huang
authors.affiliation: 1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Stephan
authors.identifier: 000000033622835X
authors.initials: S
authors.lastname: Ripke
authors.affiliation: 1] Systems and Modeling Unit, Montefiore Institute, University of Liege, Liege, Belgium. [2] Bioinformatics and Modeling, GIGA-R (Groupe Interdisciplinaire de Génoprotéomique Appliquée) Research Center, University of Liege, Liege, Belgium.
authors.forename: Elena S
authors.initials: ES
authors.lastname: Gusareva
authors.affiliation: 1] Unit of Gastroenterology, IRCCS-CSS (Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza) Hospital, San Giovanni Rotondo, Italy. [2] Unit of Gastroenterology SOD2 (Strutture Organizzative Dipartimentali), Azienda Ospedaliero Universitaria (AOU) Careggi, Florence, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Annese
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Thomsen
authors.affiliation: 1] Murdoch Children's Research Institute, Parkville, Victoria, Australia. [2] Department of Mathematics and Statistics, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Leslie
authors.affiliation: 1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: 1] Systems and Modeling Unit, Montefiore Institute, University of Liege, Liege, Belgium. [2] Bioinformatics and Modeling, GIGA-R (Groupe Interdisciplinaire de Génoprotéomique Appliquée) Research Center, University of Liege, Liege, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Steen
authors.affiliation: 1] Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. [2] Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Duerr
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Jeffrey C
authors.identifier: 000000021152370X
authors.initials: JC
authors.lastname: Barrett
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Dermot P B
authors.initials: DP
authors.lastname: McGovern
authors.affiliation: Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.
authors.forename: L Philip
authors.initials: LP
authors.lastname: Schumm
authors.affiliation: 1] Cambridge Institute for Medical Research, Cambridge, UK. [2] Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Traherne
authors.affiliation: 1] Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA. [2] Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Mary N
authors.initials: MN
authors.lastname: Carrington
authors.affiliation: 1] Department of Surgery, University of Cambridge, Cambridge, UK. [2] National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Kosmoliaptsis
authors.affiliation: 1] Research Institute of Internal Medicine, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway. [2] Norwegian Primary Sclerosing Cholangitis Research Center, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway. [3] K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: 1] Research Center, Montreal Heart Institute, Montreal, Quebec, Canada. [2] Faculté de Médecine, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
mesh_terms: D000483:Alleles; D002874:Chromosome Mapping / Q000379:methods*; D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D060005:Genotyping Techniques; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D008285:Major Histocompatibility Complex / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D059811:HLA-DRB1 Chains; C497841:HLA-DRB1*01 antigen