1. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis
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Richard H. Duerr, Dalin Li, Ming-Hsi Wang, Tariq Ahmad, John D. Rioux, Patrick Sulem, Daniel B. Graham, Steven R. Brant, Severine Vermeire, Mark Tremelling, James Lee, Leena Halme, K. de Lane, Miguel Regueiro, M Parkes, David C. Wilson, Alain Bitton, R. Milgrom, Daniel G. MacArthur, Marijn C. Visschedijk, Sören Mucha, Kenneth Croitoru, Alison Simmons, Mark S. Silverberg, Rinse K. Weersma, Jonas Halfvarson, Daniel L. Rice, J. M. Stempak, Christopher J. Hawkey, Mauro D'Amato, Christopher G. Mathew, Philippe Goyette, Frauke Degenhardt, Daniel F. Gudbjartsson, Mark J. Daly, Kari Stefansson, Beryl B. Cummings, Maarit Lappalainen, Päivi Saavalainen, Paulina Paavola-Sakki, P. Fleshner, Talin Haritunians, Joshua C. Randall, Elaine R. Nimmo, Taru Tukiainen, Christine Stevens, Subra Kugathasan, Monkol Lek, Andre Franke, Kimmo Kontula, Unnur Thorsteinsdottir, Andrew Hart, Martin O. Pollard, Gabrielle Boucher, Natalie J. Prescott, Benjamin M. Neale, Holm H. Uhlig, Carl A. Anderson, Ashwin N. Ananthakrishnan, Luke Jostins, C. Mowatt, Judy H. Cho, B. Newman, A. Nicole Desch, Yang Luo, Dermot P.B. McGovern, Clara Abraham, Ingileif Jonsdottir, Jeffrey C. Barrett, John C. Mansfield, Jean-Paul Achkar, Charlie W. Lees, Martti Färkkilä, Ramnik J. Xavier, S. R. Targan, Manuel A. Rivas, Deborah D. Proctor, Johan Van Limbergen, Nicholas A. Kennedy, Christopher A. Lamb, Jürgen Glas, Vito Annese, Yashoda Sharma, Phil Schumm, Graham A. Heap, Cathryn Edwards, Lotta L. E. Koskinen, Jack Satsangi, Mitja I. Kurki, Aarno Palotie, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA deCODE Genetics, Amgen Inc., 101 Reykjavik, Iceland Research Center, Montreal Heart Institute, Montréal, Québec, Canada H1T1C8 School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland Department of Immunology, Landspitali, the National University Hospital of Iceland, 101 Reykjavik, Iceland Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Stockholm, Sweden BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, 48903 Bilbao, Spain Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, 71013 San Giovanni Rotondo, Italy Strutture Organizzative Dipartimentali (SOD) Gastroenterologia 2, Azienda Ospedaliero Universitaria (AOU) Careggi, 50134 Florence, Italy Department of Clinical and Experimental Medicine, Translational Research in GastroIntestinal Disorders (TARGID), Katholieke Universiteit (KU) Leuven, Leuven 3000, Belgium Division of Gastroenterology, University Hospital Gasthuisberg, BE-3000 Leuven, Belgium Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, The Netherlands Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, SE 701 82 Örebro, Sweden Department of Medicine, University of Helsinki, 00100 Helsinki, Finland Helsinki University Hospital, 00100 Helsinki, Finland Clinic of Gastroenterology, Helsinki University Hospital, 00100 Helsinki, Finland Research Programs Unit, Immunobiology, and Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland Department of Transplantation and Liver Surgery, University of Helsinki, 00100 Helsinki, Finland Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00100 Helsinki, Finland Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02114, USA Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK Graham A. Heap Peninsula College of Medicine and Dentistry, Exeter PL6 8BU, UK Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21205, USA Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, 21205, USA Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA Department of Medicine, Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA Institute for Molecular Medicine Finland, University of Helsinki, 00100 Helsinki, Finland Massachusetts General Hospital, Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Boston, Massachusetts 02114, USA Research Programs Unit, Immunobiology, University of Helsinki, 00100 Helsinki, Finland Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada H3T 1J4 Department of Gastroenterology, Torbay Hospital, Devon, UK Department of Medicine, St. Mark’s Hospital, Middlesex, UK Nottingham Digestive Disease Centre, Queens Medical Centre, Nottingham, UK Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK Christ Church, University of Oxford, Oxford, UK Gastrointestinal Unit, Wester General Hospital, University of Edinburgh, Edinburgh, UK Newcastle University, Newcastle upon Tyne, UK Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, Cambridge, UK Department of Medical and Molecular Genetics, Guy’s Hospital, London, UK Department of Medical and Molecular Genetics, King’s College London School of Medicine, Guy’s Hospital, London, UK Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK Gastroenterology & General Medicine, Norfolk and Norwich University Hospital, Norwich, UK Translational Gastroenterology Unit and the Department of Pediatrics, University of Oxford, Oxford, UK Pediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK Child Life and Health, University of Edinburgh, Edinburgh, UK Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA Division of Gastroenterology, Royal Victoria Hospital, Montréal, Québec, Canada Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA, Department of Medicine, Clinicum, Gastroenterologian yksikkö, Immunobiology Research Program, Research Programs Unit, Department of Medical and Clinical Genetics, Medicum, II kirurgian klinikka, Department of Surgery, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Immunomics, Kimmo Kontula Research Group, and Genomics of Neurological and Neuropsychiatric Disorders
- Subjects
0301 basic medicine ,AAI12 ,Chemistry(all) ,SUSCEPTIBILITY LOCI ,Science ,Population ,General Physics and Astronomy ,Physics and Astronomy(all) ,OF-FUNCTION VARIANTS ,Inflammatory bowel disease ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,NUMBER ,medicine ,Ring finger ,IMPUTATION ,Allele ,education ,POPULATION ,RISK ,education.field_of_study ,Multidisciplinary ,biology ,Biochemistry, Genetics and Molecular Biology(all) ,MUTATIONS ,General Chemistry ,ASSOCIATION ,medicine.disease ,Inflammatory Bowel Diseases ,Ulcerative colitis ,digestive system diseases ,3. Good health ,Ubiquitin ligase ,Transport protein ,Transmembrane domain ,030104 developmental biology ,medicine.anatomical_structure ,RARE VARIANTS ,Immunology ,biology.protein ,Cancer research ,3111 Biomedicine ,INFLAMMATORY-BOWEL-DISEASE - Abstract
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain. National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) DK064869 DK062432 National Human Genome Research Institute (NHGRI) DK064869 DK043351 HG005923 Crohns and Colitis Foundation 3765 Leona M. & Harry B. Helmsley Charitable Trust 2015PG-IBD001 Amgen 2013583217 CCFA 3765 Cedars-Sinai F. Widjaja Foundation, info:eu-repo/grantAgreement/EC/FP7/305479, European Union DK062413 AI067068 U54DE023789-01 Leona M. and Harry B. Helmsley Charitable Trust Crohn's and Colitis Foundation of America NIH DK062431 U01 DK062429 U01 DK062422 R01 DK092235 U01 DK062420 Medical Research Council, UK MR/J00314X/1 Wellcome Trust WT091310 098051 Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh PO1DK046763
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- 2016
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