PMID- 25559196 OWN - NLM STAT- MEDLINE DCOM- 20150414 LR - 20230706 IS - 1546-1718 (Electronic) IS - 1061-4036 (Print) IS - 1061-4036 (Linking) VI - 47 IP - 2 DP - 2015 Feb TI - 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. PG - 172-9 LID - 10.1038/ng.3176 [doi] AB - 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. FAU - Goyette, Philippe AU - Goyette P AD - Research Center, Montreal Heart Institute, Montreal, Quebec, Canada. FAU - Boucher, Gabrielle AU - Boucher G AD - Research Center, Montreal Heart Institute, Montreal, Quebec, Canada. FAU - Mallon, Dermot AU - Mallon D AUID- ORCID: 0000000174341201 AD - 1] Department of Surgery, University of Cambridge, Cambridge, UK. [2] National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK. FAU - Ellinghaus, Eva AU - Ellinghaus E AUID- ORCID: 0000000329143382 AD - Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany. FAU - Jostins, Luke AU - Jostins L AD - 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK. [2] Christ Church, University of Oxford, St Aldates, UK. FAU - Huang, Hailiang AU - Huang H AUID- ORCID: 0000000314615762 AD - 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. FAU - Ripke, Stephan AU - Ripke S AUID- ORCID: 000000033622835X AD - 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. FAU - Gusareva, Elena S AU - Gusareva ES AD - 1] Systems and Modeling Unit, Montefiore Institute, University of Liege, Liege, Belgium. [2] Bioinformatics and Modeling, GIGA-R (Groupe Interdisciplinaire de Genoproteomique Appliquee) Research Center, University of Liege, Liege, Belgium. FAU - Annese, Vito AU - Annese V AD - 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. FAU - Hauser, Stephen L AU - Hauser SL AD - Department of Neurology, University of California, San Francisco, San Francisco, California, USA. FAU - Oksenberg, Jorge R AU - Oksenberg JR AD - Department of Neurology, University of California, San Francisco, San Francisco, California, USA. FAU - Thomsen, Ingo AU - Thomsen I AD - Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany. FAU - Leslie, Stephen AU - Leslie S AD - 1] Murdoch Children's Research Institute, Parkville, Victoria, Australia. [2] Department of Mathematics and Statistics, University of Melbourne, Melbourne, Victoria, Australia. CN - International Inflammatory Bowel Disease Genetics Consortium CN - Australia and New Zealand IBDGC CN - Belgium IBD Genetics Consortium CN - Italian Group for IBD Genetic Consortium CN - NIDDK Inflammatory Bowel Disease Genetics Consortium CN - United Kingdom IBDGC CN - Wellcome Trust Case Control Consortium CN - Quebec IBD Genetics Consortium FAU - Daly, Mark J AU - Daly MJ AD - 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. FAU - Van Steen, Kristel AU - Van Steen K AD - 1] Systems and Modeling Unit, Montefiore Institute, University of Liege, Liege, Belgium. [2] Bioinformatics and Modeling, GIGA-R (Groupe Interdisciplinaire de Genoproteomique Appliquee) Research Center, University of Liege, Liege, Belgium. FAU - Duerr, Richard H AU - Duerr RH AD - 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. FAU - Barrett, Jeffrey C AU - Barrett JC AUID- ORCID: 000000021152370X AD - Wellcome Trust Sanger Institute, Hinxton, UK. FAU - McGovern, Dermot P B AU - McGovern DP AD - F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. FAU - Schumm, L Philip AU - Schumm LP AD - Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA. FAU - Traherne, James A AU - Traherne JA AD - 1] Cambridge Institute for Medical Research, Cambridge, UK. [2] Department of Pathology, University of Cambridge, Cambridge, UK. FAU - Carrington, Mary N AU - Carrington MN AD - 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. FAU - Kosmoliaptsis, Vasilis AU - Kosmoliaptsis V AD - 1] Department of Surgery, University of Cambridge, Cambridge, UK. [2] National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK. FAU - Karlsen, Tom H AU - Karlsen TH AD - 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. FAU - Franke, Andre AU - Franke A AD - Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany. FAU - Rioux, John D AU - Rioux JD AD - 1] Research Center, Montreal Heart Institute, Montreal, Quebec, Canada. [2] Faculte de Medecine, Universite de Montreal, Montreal, Quebec, Canada. LA - eng GR - U54 DE023789/DE/NIDCR NIH HHS/United States GR - UL1 TR000005/TR/NCATS NIH HHS/United States GR - U01 DK062413/DK/NIDDK NIH HHS/United States GR - G0800675/MRC_/Medical Research Council/United Kingdom GR - G0600329/MRC_/Medical Research Council/United Kingdom GR - U54 DE023789-01/DE/NIDCR NIH HHS/United States GR - U01 DK062432/DK/NIDDK NIH HHS/United States GR - CZB/4/540/CSO_/Chief Scientist Office/United Kingdom GR - 102974/WT_/Wellcome Trust/United Kingdom GR - U01 DK062429-14/DK/NIDDK NIH HHS/United States GR - NIHR-RP-R3-12-026/DH_/Department of Health/United Kingdom GR - R01 CA141743/CA/NCI NIH HHS/United States GR - R01 NS049477/NS/NINDS NIH HHS/United States GR - P30 DK043351/DK/NIDDK NIH HHS/United States GR - R01 DK064869/DK/NIDDK NIH HHS/United States GR - MRF_C0482/MRF/MRF/United Kingdom GR - R01 HS021747/HS/AHRQ HHS/United States GR - ETM/137/CSO_/Chief Scientist Office/United Kingdom GR - U01 DK062429/DK/NIDDK NIH HHS/United States GR - ETM/75/CSO_/Chief Scientist Office/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - HS021747/HS/AHRQ HHS/United States GR - U01 DK062423/DK/NIDDK NIH HHS/United States GR - HHSN261200800001C/RC/CCR NIH HHS/United States GR - U01 AI067068/AI/NIAID NIH HHS/United States GR - P01 DK046763/DK/NIDDK NIH HHS/United States GR - HHSN261200800001E/CA/NCI NIH HHS/United States GR - U01 DK062420/DK/NIDDK NIH HHS/United States GR - P01 DK046763-19/DK/NIDDK NIH HHS/United States GR - U01 DK062431/DK/NIDDK NIH HHS/United States GR - WT098051/WT_/Wellcome Trust/United Kingdom GR - U19 AI067152/AI/NIAID NIH HHS/United States GR - CA141743/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. DEP - 20150105 PL - United States TA - Nat Genet JT - Nature genetics JID - 9216904 RN - 0 (HLA-DRB1 Chains) RN - 0 (HLA-DRB1*01 antigen) SB - IM MH - Alleles MH - Chromosome Mapping/*methods MH - Colitis, Ulcerative/genetics MH - Crohn Disease/genetics MH - Genetic Linkage MH - Genetic Predisposition to Disease MH - Genome-Wide Association Study MH - Genotype MH - Genotyping Techniques MH - HLA-DRB1 Chains/*genetics MH - Heterozygote MH - Humans MH - Inflammatory Bowel Diseases/*genetics MH - Major Histocompatibility Complex/*genetics MH - Phenotype MH - *Polymorphism, Single Nucleotide PMC - PMC4310771 MID - NIHMS647097 COIS- Competing Financial Interests The authors declare no competing financial interests. FIR - Abraham, Clara IR - Abraham C FIR - Achkar, Jean-Paul IR - Achkar JP FIR - Ahmad, Tariq IR - Ahmad T FIR - Amininejad, Leila IR - Amininejad L FIR - Ananthakrishnan, Ashwin N IR - Ananthakrishnan AN FIR - Andersen, Vibeke IR - Andersen V FIR - Anderson, Carl A IR - Anderson CA FIR - Andrews, Jane M IR - Andrews JM FIR - Annese, Vito IR - Annese V FIR - Aumais, Guy IR - Aumais G FIR - Baidoo, Leonard IR - Baidoo L FIR - Baldassano, Robert N IR - Baldassano RN FIR - Balschun, Tobias IR - Balschun T FIR - Bampton, Peter A IR - Bampton PA FIR - Barclay, Murray IR - Barclay M FIR - Barrett, Jeffrey C IR - Barrett JC FIR - Bayless, Theodore M IR - Bayless TM FIR - Bethge, Johannes IR - Bethge J FIR - Bis, Joshua C IR - Bis JC FIR - Bitton, Alain IR - Bitton A FIR - Boucher, Gabrielle IR - Boucher G FIR - Brand, Stephan IR - Brand S FIR - Brant, Steven R IR - Brant SR FIR - Buning, Carsten IR - Buning C FIR - Chew, Angela IR - Chew A FIR - Cho, Judy H IR - Cho JH FIR - Cleynen, Isabelle IR - Cleynen I FIR - Cohain, Ariella IR - Cohain A FIR - Croft, Anthony IR - Croft A FIR - Daly, Mark J IR - Daly MJ FIR - D'Amato, Mauro IR - D'Amato M FIR - Danese, Silvio IR - Danese S FIR - De Jong, Dirk IR - De Jong D FIR - De Vos, Martine IR - De Vos M FIR - Denapiene, Goda IR - Denapiene G FIR - Denson, Lee A IR - Denson LA FIR - Devaney, Kathy L IR - Devaney KL FIR - Dewit, Olivier IR - Dewit O FIR - D'Inca, Renata IR - D'Inca R FIR - Dubinsky, Marla IR - Dubinsky M FIR - Duerr, Richard H IR - Duerr RH FIR - Edwards, Cathryn IR - Edwards C FIR - Ellinghaus, David IR - Ellinghaus D FIR - Essers, Jonah IR - Essers J FIR - Ferguson, Lynnette R IR - Ferguson LR FIR - Festen, Eleonora A IR - Festen EA FIR - Fleshner, Philip IR - Fleshner P FIR - Florin, Tim IR - Florin T FIR - Franchimont, Denis IR - Franchimont D FIR - Franke, Andre IR - Franke A FIR - Fransen, Karin IR - Fransen K FIR - Gearry, Richard IR - Gearry R FIR - Georges, Michel IR - Georges M FIR - Gieger, Christian IR - Gieger C FIR - Glas, Jurgen IR - Glas J FIR - Goyette, Philippe IR - Goyette P FIR - Green, Todd IR - Green T FIR - Griffiths, Anne M IR - Griffiths AM FIR - Guthery, Stephen L IR - Guthery SL FIR - Hakonarson, Hakon IR - Hakonarson H FIR - Halfvarson, Jonas IR - Halfvarson J FIR - Hanigan, Katherine IR - Hanigan K FIR - Haritunians, Talin IR - Haritunians T FIR - Hart, Ailsa IR - Hart A FIR - Hawkey, Chris IR - Hawkey C FIR - Hayward, Nicholas K IR - Hayward NK FIR - Hedl, Matija IR - Hedl M FIR - Henderson, Paul IR - Henderson P FIR - Hu, Xinli IR - Hu X FIR - Huang, Hailiang IR - Huang H FIR - Hui, Ken Y IR - Hui KY FIR - Imielinski, Marcin IR - Imielinski M FIR - Ippoliti, Andrew IR - Ippoliti A FIR - Jonaitis, Laimas IR - Jonaitis L FIR - Jostins, Luke IR - Jostins L FIR - Karlsen, Tom H IR - Karlsen TH FIR - Kennedy, Nicholas A IR - Kennedy NA FIR - Khan, Mohammed Azam IR - Khan MA FIR - Kiudelis, Gediminas IR - Kiudelis G FIR - Kugathasan, Subra IR - Kugathasan S FIR - Kupcinskas, Limas IR - Kupcinskas L FIR - Latiano, Anna IR - Latiano A FIR - Laukens, Debby IR - Laukens D FIR - Lawrance, Ian C IR - Lawrance IC FIR - Lee, James C IR - Lee JC FIR - Lees, Charlie W IR - Lees CW FIR - Leja, Marcis IR - Leja M FIR - Van Limbergen, Johan IR - Van Limbergen J FIR - Lionetti, Paolo IR - Lionetti P FIR - Liu, Jimmy Z IR - Liu JZ FIR - Mahy, Gillian IR - Mahy G FIR - Mansfield, John IR - Mansfield J FIR - Massey, Dunecan IR - Massey D FIR - Mathew, Christopher G IR - Mathew CG FIR - McGovern, Dermot P B IR - McGovern DP FIR - Milgrom, Raquel IR - Milgrom R FIR - Mitrovic, Mitja IR - Mitrovic M FIR - Montgomery, Grant W IR - Montgomery GW FIR - Mowat, Craig IR - Mowat C FIR - Newman, William IR - Newman W FIR - Ng, Aylwin IR - Ng A FIR - Ng, Siew C IR - Ng SC FIR - Ng, Sok Meng Evelyn IR - Ng SM FIR - Nikolaus, Susanna IR - Nikolaus S FIR - Ning, Kaida IR - Ning K FIR - Nothen, Markus IR - Nothen M FIR - Oikonomou, Ioannis IR - Oikonomou I FIR - Palmieri, Orazio IR - Palmieri O FIR - Parkes, Miles IR - Parkes M FIR - Phillips, Anne IR - Phillips A FIR - Ponsioen, Cyriel Y IR - Ponsioen CY FIR - Potocnik, Uros IR - Potocnik U FIR - Prescott, Natalie J IR - Prescott NJ FIR - Proctor, Deborah D IR - Proctor DD FIR - Radford-Smith, Graham IR - Radford-Smith G FIR - Rahier, Jean-Francois IR - Rahier JF FIR - Raychaudhuri, Soumya IR - Raychaudhuri S FIR - Regueiro, Miguel IR - Regueiro M FIR - Rieder, Florian IR - Rieder F FIR - Rioux, John D IR - Rioux JD FIR - Ripke, Stephan IR - Ripke S FIR - Roberts, Rebecca IR - Roberts R FIR - Russell, Richard K IR - Russell RK FIR - Sanderson, Jeremy D IR - Sanderson JD FIR - Sans, Miquel IR - Sans M FIR - Satsangi, Jack IR - Satsangi J FIR - Schadt, Eric E IR - Schadt EE FIR - Schreiber, Stefan IR - Schreiber S FIR - Schumm, L Philip IR - Schumm LP FIR - Scott, Regan IR - Scott R FIR - Seielstad, Mark IR - Seielstad M FIR - Sharma, Yashoda IR - Sharma Y FIR - Silverberg, Mark S IR - Silverberg MS FIR - Simms, Lisa A IR - Simms LA FIR - Skieceviciene, Jurgita IR - Skieceviciene J FIR - Spain, Sarah L IR - Spain SL FIR - Steinhart, A Hillary IR - Steinhart AH FIR - Stempak, Joanne M IR - Stempak JM FIR - Stronati, Laura IR - Stronati L FIR - Sventoraityte, Jurgita IR - Sventoraityte J FIR - Targan, Stephan R IR - Targan SR FIR - Taylor, Kirstin M IR - Taylor KM FIR - Velde, Anje ter IR - Velde At FIR - Theatre, Emilie IR - Theatre E FIR - Torkvist, Leif IR - Torkvist L FIR - Tremelling, Mark IR - Tremelling M FIR - van der Meulen, Andrea IR - van der Meulen A FIR - van Sommeren, Suzanne IR - van Sommeren S FIR - Vasiliauskas, Eric IR - Vasiliauskas E FIR - Vermeire, Severine IR - Vermeire S FIR - Verspaget, Hein W IR - Verspaget HW FIR - Walters, Thomas IR - Walters T FIR - Wang, Kai IR - Wang K FIR - Wang, Ming-Hsi IR - Wang MH FIR - Weersma, Rinse K IR - Weersma RK FIR - Wei, Zhi IR - Wei Z FIR - Whiteman, David IR - Whiteman D FIR - Wijmenga, Cisca IR - Wijmenga C FIR - Wilson, David C IR - Wilson DC FIR - Winkelmann, Juliane IR - Winkelmann J FIR - Xavier, Ramnik J IR - Xavier RJ FIR - Zeissig, Sebastian IR - Zeissig S FIR - Zhang, Bin IR - Zhang B FIR - Zhang, Clarence K IR - Zhang CK FIR - Zhang, Hu IR - Zhang H FIR - Zhang, Wei IR - Zhang W FIR - Zhao, Hongyu IR - Zhao H FIR - Zhao, Zhen Z IR - Zhao ZZ EDAT- 2015/01/07 06:00 MHDA- 2015/04/15 06:00 PMCR- 2015/08/01 CRDT- 2015/01/07 06:00 PHST- 2014/07/08 00:00 [received] PHST- 2014/12/04 00:00 [accepted] PHST- 2015/01/07 06:00 [entrez] PHST- 2015/01/07 06:00 [pubmed] PHST- 2015/04/15 06:00 [medline] PHST- 2015/08/01 00:00 [pmc-release] AID - ng.3176 [pii] AID - 10.1038/ng.3176 [doi] PST - ppublish SO - Nat Genet. 2015 Feb;47(2):172-9. doi: 10.1038/ng.3176. Epub 2015 Jan 5.