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, Clara Abraham, Jean-Paul Achkar, Tariq Ahmad, Leila Amininejad, Ashwin N. Ananthakrishnan, Vibeke Andersen, Carl A. Anderson, Jane M. Andrews, Guy Aumais, Leonard Baidoo, Robert N. Baldassano, Tobias Balschun, Peter A. Bampton, Murray Barclay, Theodore M. Bayless, Johannes Bethge, Joshua C. Bis, Alain Bitton, Stephan Brand, Steven R. Brant, Carsten Buning, Angela Chew, Judy H. Cho, Isabelle Cleynen, Ariella Cohain, Anthony Croft, Mauro D'Amato, Silvio Danese, Dirk De Jong, Martine De Vos, Goda Denapiene, Lee A. Denson, Kathy L. Devaney, Olivier Dewit, Renata D'Inca, Marla Dubinsky, Cathryn Edwards, David Ellinghaus, Jonah Essers, Lynnette R. Ferguson, Eleonora A. Festen, Philip Fleshner, Tim Florin, Denis Franchimont, Karin Fransen, Richard Gearry, Michel Georges, Christian Gieger, Jurgen Glas, Todd Green, Anne M. Griffiths, Stephen L. Guthery, Hakon Hakonarson, Jonas Halfvarson, Katherine Hanigan, Talin Haritunians, Ailsa Hart, Chris Hawkey, Nicholas K. Hayward, Matija Hedl, Paul Henderson, Xinli Hu, Ken Y. Hui, Marcin Imielinski, Andrew Ippoliti, Laimas Jonaitis, Nicholas A. Kennedy, Mohammed Azam Khan, Gediminas Kiudelis, Subra Kugathasan, Limas Kupcinskas, Anna Latiano, Debby Laukens, Ian C. Lawrance, James C. Lee, Charlie W. Lees, Marcis Leja, Johan Van Limbergen, Paolo Lionetti, Jimmy Z. Liu, Edouard Louis, Gillian Mahy, John Mansfield, Dunecan Massey, Christopher G. Mathew, Raquel Milgrom, Mitja Mitrovic, Grant Montgomery, Craig Mowat, Wwilliam Newman, Aylwin Ng, Siew C. Ng, Sok Meng Evelyn Ng, Susanna Nikolaus, Kaida Ning, Markus Nothen, Ioannis Oikonomou, Orazio Palmieri, Miles Parkes, Anne Phillips, Cyriel Y. Ponsioen, Uros Potocnik, Natalie J. Prescott, Deborah D. Proctor, Graham Radford-Smith, Jean-Francois Rahier, Soumya Raychaudhur, Miguel Regueiro, Florian Rieder, Rebecca Roberts, Richard K. Russell, Jeremy D. Sanderson, Miquel Sans, Jack Satsangi, Eric E. Schadt, Stefan Schreiber, L. Philip Schumm, Regan Scott, Mark Seielstad, Yashoda Sharma, Mark S. Silverberg, Lisa A. Simms, Jurgita Skieceviciene, Sarah L. Spain, A. Hillary Steinhart, Joanne M. Stempak, Laura Stronati, Jurgita Sventoraityte, Stephan R. Targan, Kirstin M. Taylor, Anje Ter Velde, Emilie Theatre, Leif Torkvist, Mark Tremelling, Andrea Van Der Meulen, Suzanne Van Sommeren, Eric Vasiliauskas, Severine Vermeire, Hein W. Verspaget, Thomas Walters, Kai Wwang, Ming-Hsi Wwang, Rinse K. Wweersma, Zhi Wei, David Whiteman, Cisca Wijmenga, David C. Wilson, Juliane Winkelmann, Ramnik J. Xavier, Sebastian Zeissig, Bin Zhang, Clarence K. Zhang, Hu Zhang, Wwei Zhang, Hongyu Zhao, Zhen Z. Zhao

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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 - 179
Number of pages8
JournalNature Genetics
Volume47
Issue number2
DOIs
Publication statusPublished - 1 Jan 2015
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Goyette, P., Boucher, G., Mallon, D., Ellinghaus, E., Jostins, L., Huang, H., Ripke, S., Gusareva, E. S., Annese, V., Hauser, S. L., Oksenberg, J. R., Thomsen, I., Leslie, S., Daly, M. J., Van Steen, K., Duerr, R. H., Barrett, J. C., McGovern, D. P. B., Schumm, L. P., ... Zhao, Z. Z. (2015). 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. Nature Genetics, 47(2), 172 - 179. https://doi.org/10.1038/ng.3176