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Nat Genet. 2015 Feb;47(2):172-9. doi: 10.1038/ng.3176. Epub 2015 Jan 5.

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.

Collaborators (168)

Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Anderson CA, Andrews JM, Annese V, Aumais G, Baidoo L, Baldassano RN, Balschun T, Bampton PA, Barclay M, Barrett JC, Bayless TM, Bethge J, Bis JC, Bitton A, Boucher G, Brand S, Brant SR, Büning C, Chew A, Cho JH, Cleynen I, Cohain A, Croft A, Daly MJ, D'Amato M, Danese S, De Jong D, De Vos M, Denapiene G, Denson LA, Devaney KL, Dewit O, D'Inca R, Dubinsky M, Duerr RH, Edwards C, Ellinghaus D, Essers J, Ferguson LR, Festen EA, Fleshner P, Florin T, Franchimont D, Franke A, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Goyette P, Green T, Griffiths AM, Guthery SL, Hakonarson H, Halfvarson J, Hanigan K, Haritunians T, Hart A, Hawkey C, Hayward NK, Hedl M, Henderson P, Hu X, Huang H, Hui KY, Imielinski M, Ippoliti A, Jonaitis L, Jostins L, Karlsen TH, Kennedy NA, Khan MA, Kiudelis G, Kugathasan S, Kupcinskas L, Latiano A, Laukens D, Lawrance IC, Lee JC, Lees CW, Leja M, Van Limbergen J, Lionetti P, Liu JZ, Mahy G, Mansfield J, Massey D, Mathew CG, McGovern DP, Milgrom R, Mitrovic M, Montgomery GW, Mowat C, Newman W, Ng A, Ng SC, Ng SM, Nikolaus S, Ning K, Nöthen M, Oikonomou I, Palmieri O, Parkes M, Phillips A, Ponsioen CY, Potocnik U, Prescott NJ, Proctor DD, Radford-Smith G, Rahier JF, Raychaudhuri S, Regueiro M, Rieder F, Rioux JD, Ripke S, Roberts R, Russell RK, Sanderson JD, Sans M, Satsangi J, Schadt EE, Schreiber S, Schumm LP, Scott R, Seielstad M, Sharma Y, Silverberg MS, Simms LA, Skieceviciene J, Spain SL, Steinhart AH, Stempak JM, Stronati L, Sventoraityte J, Targan SR, Taylor KM, Velde At, Theatre E, Torkvist L, Tremelling M, van der Meulen A, van Sommeren S, Vasiliauskas E, Vermeire S, Verspaget HW, Walters T, Wang K, Wang MH, Weersma RK, Wei Z, Whiteman D, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhang H, Zhang W, Zhao H, Zhao ZZ.

Author information

Research Center, Montreal Heart Institute, Montreal, Quebec, Canada.
1] Department of Surgery, University of Cambridge, Cambridge, UK. [2] National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK.
Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany.
1] Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK. [2] Christ Church, University of Oxford, St Aldates, UK.
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.
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.
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.
Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
1] Murdoch Children's Research Institute, Parkville, Victoria, Australia. [2] Department of Mathematics and Statistics, University of Melbourne, Melbourne, Victoria, Australia.
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.
Wellcome Trust Sanger Institute, Hinxton, UK.
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.
1] Cambridge Institute for Medical Research, Cambridge, UK. [2] Department of Pathology, University of Cambridge, Cambridge, UK.
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.
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.
1] Research Center, Montreal Heart Institute, Montreal, Quebec, Canada. [2] Faculté de Médecine, Université de Montréal, Montreal, Quebec, Canada.


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.

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