TY - JOUR
T1 - 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
AU - Australia and New Zealand IBDGC
AU - Belgium IBD Genetics Consortium
AU - Italian Group for IBD Genetic Consortium
AU - NIDDK Inflammatory Bowel Disease Genetics Consortium
AU - United Kingdom IBDGC
AU - Wwellcome Trust Case Control Consortium &Quebec IBD Genetics Consortium
AU - Goyette, Philippe
AU - Boucher, Gabrielle
AU - Mallon, Dermot
AU - Ellinghaus, Eva
AU - Jostins, Luke
AU - Huang, Hailiang
AU - Ripke, Stephan
AU - Gusareva, Elena S.
AU - Annese, Vito
AU - Hauser, Stephen L.
AU - Oksenberg, Jorge R.
AU - Thomsen, Ingo
AU - Leslie, Stephen
AU - Daly, Mark J.
AU - Van Steen, Kristel
AU - Duerr, Richard H.
AU - Barrett, Jeffrey C.
AU - McGovern, Dermot P.B.
AU - Schumm, L. Philip
AU - Traherne, James A.
AU - Carrington, Mary N.
AU - Kosmoliaptsis, Vasilis
AU - Karlsen, Tom H.
AU - Franke, Andre
AU - Rioux, John D.
AU - Abraham, Clara
AU - Achkar, Jean Paul
AU - Ahmad, Tariq
AU - Amininejad, Leila
AU - Ananthakrishnan, Ashwin N.
AU - Andersen, Vibeke
AU - Anderson, Carl A.
AU - Andrews, Jane M.
AU - Aumais, Guy
AU - Baidoo, Leonard
AU - Baldassano, Robert N.
AU - Balschun, Tobias
AU - Bampton, Peter A.
AU - Barclay, Murray
AU - Bayless, Theodore M.
AU - Bethge, Johannes
AU - Bis, Joshua C.
AU - Bitton, Alain
AU - Brand, Stephan
AU - Brant, Steven R.
AU - Buning, Carsten
AU - Chew, Angela
AU - Cho, Judy H.
AU - Cleynen, Isabelle
AU - Hui, Ken Y.
N1 - Funding Information:
We would like to thank the International PSC study group (http://www.ipscsg. org/) for sharing data. We are grateful to B.A. Lie and K. Holm for helpful discussions. J.D.R. holds a Canada Research Chair, and this work was supported by a US National Institute of Diabetes and Digestive and Kidney Diseases grant (NIDDK; R01 DK064869 and U01 DK062432). The laboratory of A.F. is supported by the German Ministry of Education and Research (BMBF) grant program e: Med (sysINFLAME). A.F. receives infrastructure support from the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence ‘Inflammation at Interfaces’ and holds an endowment professorship (Peter Hans Hofschneider Professorship) of the Foundation for Experimental Biomedicine (Zurich, Switzerland). Grant support for T.H.K. and A.F. was received from the European Union Seventh Framework Programme (FP7/2007-2013, grant number 262055, ESGI). M.N.C. is supported by the Intramural Research Program of the US National Institutes of Health (NIH), Frederick National Laboratory, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. J.C.B. was supported by a Wellcome Trust grant (WT098051). D.M. and V.K. are supported by the NIHR Cambridge Biomedical Research Centre. L.P.S. is supported by an NIDDK grant (U01 DK062429-14). J.A.T. is supported by the UK Medical Research Council. D.P.B.M. is supported by the Leona M. and Harry B. Helmsley Charitable Trust, the European Union (305479) and by grants from the NIDDK (U01 DK062413, P01 DK046763-19, U54 DE023789-01), the National Institute of Allergy and Infectious Diseases (NIAID; U01 AI067068) and the Agency for Healthcare Research and Quality (AHRQ; HS021747). R.H.D. holds the Inflammatory Bowel Disease Genetic Research endowed chair at the University of Pittsburgh and was supported by an NIDDK grant (U01 DK062420) and a US National Cancer Institute grant (CA141743). S.L.H. and J.R.O. would like to also acknowledge the support of the US NIH (R01 NS049477 and 1U19 A1067152) and the National Multiple Sclerosis Society (RG 2899-D11). S.L. wishes to acknowledge support from the Australian National Health and Medical Research Council (R.D. Wright Career Development Fellowship, APP1053756).
Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84928612813&partnerID=8YFLogxK
U2 - 10.1038/ng.3176
DO - 10.1038/ng.3176
M3 - Article
C2 - 25559196
AN - SCOPUS:84928612813
SN - 1061-4036
VL - 47
SP - 172
EP - 179
JO - Nature genetics
JF - Nature genetics
IS - 2
ER -