A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-08-09

AUTHORS

Manuel A. Rivas, Daniel Graham, Patrick Sulem, Christine Stevens, A. Nicole Desch, Philippe Goyette, Daniel Gudbjartsson, Ingileif Jonsdottir, Unnur Thorsteinsdottir, Frauke Degenhardt, Sören Mucha, Mitja I. Kurki, Dalin Li, Mauro D’Amato, Vito Annese, Severine Vermeire, Rinse K. Weersma, Jonas Halfvarson, Paulina Paavola-Sakki, Maarit Lappalainen, Monkol Lek, Beryl Cummings, Taru Tukiainen, Talin Haritunians, Leena Halme, Lotta L. E. Koskinen, Ashwin N. Ananthakrishnan, Yang Luo, Graham A. Heap, Marijn C. Visschedijk, Daniel G. MacArthur, Benjamin M. Neale, Tariq Ahmad, Carl A. Anderson, Steven R. Brant, Richard H. Duerr, Mark S. Silverberg, Judy H Cho, Aarno Palotie, Päivi Saavalainen, Kimmo Kontula, Martti Färkkilä, Dermot P. B. McGovern, Andre Franke, Kari Stefansson, John D. Rioux, Ramnik J. Xavier, Mark J. Daly

ABSTRACT

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. More... »

PAGES

12342

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  • Journal

    TITLE

    Nature Communications

    ISSUE

    1

    VOLUME

    7

    Author Affiliations

  • Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, Massachusetts, USA
  • Broad Institute of MIT and Harvard, 02142, Cambridge, Massachusetts, USA
  • deCODE Genetics, Amgen Inc., 101, Reykjavik, Iceland
  • Research Center, Montreal Heart Institute, H1T1C8, Montréal, Québec, Canada
  • School of Engineering and Natural Sciences, University 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
  • Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 90048, Los Angeles, California, USA
  • BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, 48903, Bilbao, Spain
  • Strutture Organizzative Dipartimentali (SOD) Gastroenterologia 2, Azienda Ospedaliero Universitaria (AOU) Careggi, 50134, Florence, Italy
  • 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
  • Clinic of Gastroenterology, Helsinki University Hospital, 00100, Helsinki, Finland
  • and Department of Medical and Clinical Genetics, Research Programs Unit, Immunobiology, 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
  • Division of Medical Sciences, Harvard Medical School, 02114, Boston, Massachusetts, USA
  • Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, CB10 1SA, Hinxton, UK
  • IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, EX2 5DW, Exeter, UK
  • Peninsula College of Medicine and Dentistry, PL6 8BU, Exeter, UK
  • Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, 21205, Baltimore, Maryland, USA
  • Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, 15261, Pittsburgh, Pennsylvania, USA
  • Department of Medicine, Inflammatory Bowel Disease Centre, Mount Sinai Hospital, M5G 1X5, Toronto, Ontario, Canada
  • Department of Genetics, Yale School of Medicine, 06510, New Haven, Connecticut, USA
  • Massachusetts General Hospital, Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, 02114, Boston, Massachusetts, USA
  • Research Programs Unit, Immunobiology, University of Helsinki, 00100, Helsinki, Finland
  • Helsinki University Hospital, 00100, Helsinki, Finland
  • Faculté de Médecine, Université de Montréal, H3T 1J4, Montréal, Québec, Canada
  • Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, Massachusetts, USA
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ncomms12342

    DOI

    http://dx.doi.org/10.1038/ncomms12342

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1027472955

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/27503255


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