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

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 and Mark J. Daly ()
Additional contact information
Manuel A. Rivas: Broad Institute of MIT and Harvard
Daniel Graham: Broad Institute of MIT and Harvard
Patrick Sulem: deCODE Genetics, Amgen Inc.
Christine Stevens: Broad Institute of MIT and Harvard
A. Nicole Desch: Broad Institute of MIT and Harvard
Philippe Goyette: Research Center, Montreal Heart Institute
Daniel Gudbjartsson: deCODE Genetics, Amgen Inc.
Ingileif Jonsdottir: deCODE Genetics, Amgen Inc.
Unnur Thorsteinsdottir: deCODE Genetics, Amgen Inc.
Frauke Degenhardt: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel
Sören Mucha: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel
Mitja I. Kurki: Broad Institute of MIT and Harvard
Dalin Li: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center
Mauro D’Amato: Karolinska Institutet
Vito Annese: Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital
Severine Vermeire: Translational Research in GastroIntestinal Disorders (TARGID), Katholieke Universiteit (KU) Leuven
Rinse K. Weersma: University of Groningen and University Medical Center Groningen
Jonas Halfvarson: Faculty of Medicine and Health, Örebro University
Paulina Paavola-Sakki: University of Helsinki
Maarit Lappalainen: University of Helsinki
Monkol Lek: Broad Institute of MIT and Harvard
Beryl Cummings: Broad Institute of MIT and Harvard
Taru Tukiainen: Broad Institute of MIT and Harvard
Talin Haritunians: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center
Leena Halme: University of Helsinki
Lotta L. E. Koskinen: Research Programs Unit, Immunobiology, University of Helsinki
Ashwin N. Ananthakrishnan: Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School
Yang Luo: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Graham A. Heap: IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust
Marijn C. Visschedijk: University of Groningen and University Medical Center Groningen
Daniel G. MacArthur: Broad Institute of MIT and Harvard
Benjamin M. Neale: Broad Institute of MIT and Harvard
Tariq Ahmad: Peninsula College of Medicine and Dentistry
Carl A. Anderson: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Steven R. Brant: Meyerhoff Inflammatory Bowel Disease Center, School of Medicine, Johns Hopkins University
Richard H. Duerr: Hepatology and Nutrition, University of Pittsburgh School of Medicine
Mark S. Silverberg: Inflammatory Bowel Disease Centre, Mount Sinai Hospital
Judy H Cho: Yale School of Medicine
Aarno Palotie: Broad Institute of MIT and Harvard
Päivi Saavalainen: Research Programs Unit, Immunobiology, University of Helsinki
Kimmo Kontula: University of Helsinki
Martti Färkkilä: University of Helsinki
Dermot P. B. McGovern: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center
Andre Franke: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel
Kari Stefansson: deCODE Genetics, Amgen Inc.
John D. Rioux: Research Center, Montreal Heart Institute
Ramnik J. Xavier: Broad Institute of MIT and Harvard
Mark J. Daly: Broad Institute of MIT and Harvard

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12342

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