. 2016 Aug 9:7:12342.

doi: 10.1038/ncomms12342.

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

Manuel A Rivas^{1

2}, Daniel Graham¹, Patrick Sulem³, Christine Stevens¹, A Nicole Desch¹, Philippe Goyette⁴, Daniel Gudbjartsson^{3

5}, Ingileif Jonsdottir^{3

6

7}, Unnur Thorsteinsdottir^{3

7}, Frauke Degenhardt⁸, Sören Mucha⁸, Mitja I Kurki^{1

2}, Dalin Li^{9

10}, Mauro D'Amato^{11

12}, Vito Annese^{13

14}, Severine Vermeire^{15

16}, Rinse K Weersma¹⁷, Jonas Halfvarson¹⁸, Paulina Paavola-Sakki^{19

20

21}, Maarit Lappalainen^{19

20

22}, Monkol Lek^{1

2}, Beryl Cummings^{1

2}, Taru Tukiainen^{1

2}, Talin Haritunians^{9

10}, Leena Halme²³, Lotta L E Koskinen^{22

24}, Ashwin N Ananthakrishnan^{25

26}, Yang Luo²⁷, Graham A Heap²⁸, Marijn C Visschedijk¹⁷; UK IBD Genetics Consortium; NIDDK IBD Genetics Consortium; Daniel G MacArthur^{1

2}, Benjamin M Neale^{1

2}, Tariq Ahmad²⁹, Carl A Anderson²⁷, Steven R Brant^{30

31}, Richard H Duerr^{32

33}, Mark S Silverberg³⁴, Judy H Cho³⁵, Aarno Palotie^{1

2

36

37}, Päivi Saavalainen³⁸, Kimmo Kontula^{19

20}, Martti Färkkilä^{19

20

21}, Dermot P B McGovern^{9

10}, Andre Franke⁸, Kari Stefansson^{3

7}, John D Rioux^{4

39}, Ramnik J Xavier^{1

25}, Mark J Daly^{1

2}, J Barrett²⁸, K de Lane²⁸, C Edwards⁴⁰, A Hart⁴¹, C Hawkey⁴², L Jostins^{43

44}, N Kennedy⁴⁵, C Lamb⁴⁶, J Lee⁴⁷, C Lees⁴⁵, J Mansfield⁴⁶, C Mathew^{48

49}, C Mowatt⁵⁰, B Newman^{51

52}, E Nimmo⁵³, M Parkes⁴⁷, M Pollard²⁸, N Prescott^{48

49}, J Randall²⁸, D Rice²⁸, J Satsangi⁵³, A Simmons^{54

55}, M Tremelling⁵⁶, H Uhlig⁵⁷, D Wilson^{58

59}, C Abraham⁶⁰, J P Achkar^{61

62}, A Bitton⁶³, G Boucher⁴, K Croitoru⁶⁴, P Fleshner²³, J Glas⁶³, S Kugathasan⁶⁵, J V Limbergen⁶⁶, R Milgrom³⁵, D Proctor⁶⁰, M Regueiro³³, P L Schumm⁶⁷, Y Sharma⁶⁸, J M Stempak³⁵, S R Targan²³, M H Wang³²

Collaborators, Affiliations

Collaborators

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
³ deCODE Genetics, Amgen Inc., 101 Reykjavik, Iceland.
⁴ Research Center, Montreal Heart Institute, Montréal, Québec, Canada H1T1C8.
⁵ School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland.
⁶ Department of Immunology, Landspitali, the National University Hospital of Iceland, 101 Reykjavik, Iceland.
⁷ Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
⁸ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany.
⁹ F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
¹⁰ Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA.
¹¹ Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Stockholm, Sweden.
¹² BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, 48903 Bilbao, Spain.
¹³ Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, 71013 San Giovanni Rotondo, Italy.
¹⁴ Strutture Organizzative Dipartimentali (SOD) Gastroenterologia 2, Azienda Ospedaliero Universitaria (AOU) Careggi, 50134 Florence, Italy.
¹⁵ Department of Clinical and Experimental Medicine, Translational Research in GastroIntestinal Disorders (TARGID), Katholieke Universiteit (KU) Leuven, Leuven 3000, Belgium.
¹⁶ Division of Gastroenterology, University Hospital Gasthuisberg, BE-3000 Leuven, Belgium.
¹⁷ Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.
¹⁸ Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, SE 701 82 Örebro, Sweden.
¹⁹ Department of Medicine, University of Helsinki, 00100 Helsinki, Finland.
²⁰ Helsinki University Hospital, 00100 Helsinki, Finland.
²¹ Clinic of Gastroenterology, Helsinki University Hospital, 00100 Helsinki, Finland.
²² Research Programs Unit, Immunobiology, and Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland.
²³ Department of Transplantation and Liver Surgery, University of Helsinki, 00100 Helsinki, Finland.
²⁴ Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00100 Helsinki, Finland.
²⁵ Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
²⁶ Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02114, USA.
²⁷ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
²⁸ IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
²⁹ Peninsula College of Medicine and Dentistry, Exeter PL6 8BU, UK.
³⁰ Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21205, USA.
³¹ Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, 21205, USA.
³² Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
³³ Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA.
³⁴ Department of Medicine, Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
³⁵ Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.
³⁶ Institute for Molecular Medicine Finland, University of Helsinki, 00100 Helsinki, Finland.
³⁷ Massachusetts General Hospital, Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Boston, Massachusetts 02114, USA.
³⁸ Research Programs Unit, Immunobiology, University of Helsinki, 00100 Helsinki, Finland.
³⁹ Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada H3T 1J4.
⁴⁰ Department of Gastroenterology, Torbay Hospital, Devon, UK.
⁴¹ Department of Medicine, St. Mark's Hospital, Middlesex, UK.
⁴² Nottingham Digestive Disease Centre, Queens Medical Centre, Nottingham, UK.
⁴³ Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK.
⁴⁴ Christ Church, University of Oxford, Oxford, UK.
⁴⁵ Gastrointestinal Unit, Wester General Hospital, University of Edinburgh, Edinburgh, UK.
⁴⁶ Newcastle University, Newcastle upon Tyne, UK.
⁴⁷ Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK.
⁴⁸ Department of Medical and Molecular Genetics, Guy's Hospital, London, UK.
⁴⁹ Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.
⁵⁰ Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK.
⁵¹ Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK.
⁵² The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
⁵³ Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
⁵⁴ Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.
⁵⁵ Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
⁵⁶ Gastroenterology &General Medicine, Norfolk and Norwich University Hospital, Norwich, UK.
⁵⁷ Translational Gastroenterology Unit and the Department of Pediatrics, University of Oxford, Oxford, UK.
⁵⁸ Pediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK.
⁵⁹ Child Life and Health, University of Edinburgh, Edinburgh, UK.
⁶⁰ Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
⁶¹ Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁶² Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁶³ Division of Gastroenterology, Royal Victoria Hospital, Montréal, Québec, Canada.
⁶⁴ Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
⁶⁵ Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
⁶⁶ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada.
⁶⁷ Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.
⁶⁸ Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

PMID: 27503255
PMCID: PMC4980482
DOI: 10.1038/ncomms12342

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

Manuel A Rivas et al. Nat Commun. 2016.

. 2016 Aug 9:7:12342.

doi: 10.1038/ncomms12342.

Authors

Collaborators

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
³ deCODE Genetics, Amgen Inc., 101 Reykjavik, Iceland.
⁴ Research Center, Montreal Heart Institute, Montréal, Québec, Canada H1T1C8.
⁵ School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland.
⁶ Department of Immunology, Landspitali, the National University Hospital of Iceland, 101 Reykjavik, Iceland.
⁷ Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
⁸ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany.
⁹ F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
¹⁰ Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA.
¹¹ Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Stockholm, Sweden.
¹² BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, 48903 Bilbao, Spain.
¹³ Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, 71013 San Giovanni Rotondo, Italy.
¹⁴ Strutture Organizzative Dipartimentali (SOD) Gastroenterologia 2, Azienda Ospedaliero Universitaria (AOU) Careggi, 50134 Florence, Italy.
¹⁵ Department of Clinical and Experimental Medicine, Translational Research in GastroIntestinal Disorders (TARGID), Katholieke Universiteit (KU) Leuven, Leuven 3000, Belgium.
¹⁶ Division of Gastroenterology, University Hospital Gasthuisberg, BE-3000 Leuven, Belgium.
¹⁷ Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.
¹⁸ Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, SE 701 82 Örebro, Sweden.
¹⁹ Department of Medicine, University of Helsinki, 00100 Helsinki, Finland.
²⁰ Helsinki University Hospital, 00100 Helsinki, Finland.
²¹ Clinic of Gastroenterology, Helsinki University Hospital, 00100 Helsinki, Finland.
²² Research Programs Unit, Immunobiology, and Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland.
²³ Department of Transplantation and Liver Surgery, University of Helsinki, 00100 Helsinki, Finland.
²⁴ Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00100 Helsinki, Finland.
²⁵ Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
²⁶ Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02114, USA.
²⁷ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
²⁸ IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
²⁹ Peninsula College of Medicine and Dentistry, Exeter PL6 8BU, UK.
³⁰ Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21205, USA.
³¹ Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, 21205, USA.
³² Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
³³ Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA.
³⁴ Department of Medicine, Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
³⁵ Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.
³⁶ Institute for Molecular Medicine Finland, University of Helsinki, 00100 Helsinki, Finland.
³⁷ Massachusetts General Hospital, Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Boston, Massachusetts 02114, USA.
³⁸ Research Programs Unit, Immunobiology, University of Helsinki, 00100 Helsinki, Finland.
³⁹ Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada H3T 1J4.
⁴⁰ Department of Gastroenterology, Torbay Hospital, Devon, UK.
⁴¹ Department of Medicine, St. Mark's Hospital, Middlesex, UK.
⁴² Nottingham Digestive Disease Centre, Queens Medical Centre, Nottingham, UK.
⁴³ Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK.
⁴⁴ Christ Church, University of Oxford, Oxford, UK.
⁴⁵ Gastrointestinal Unit, Wester General Hospital, University of Edinburgh, Edinburgh, UK.
⁴⁶ Newcastle University, Newcastle upon Tyne, UK.
⁴⁷ Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK.
⁴⁸ Department of Medical and Molecular Genetics, Guy's Hospital, London, UK.
⁴⁹ Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.
⁵⁰ Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK.
⁵¹ Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK.
⁵² The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
⁵³ Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
⁵⁴ Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.
⁵⁵ Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
⁵⁶ Gastroenterology &General Medicine, Norfolk and Norwich University Hospital, Norwich, UK.
⁵⁷ Translational Gastroenterology Unit and the Department of Pediatrics, University of Oxford, Oxford, UK.
⁵⁸ Pediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK.
⁵⁹ Child Life and Health, University of Edinburgh, Edinburgh, UK.
⁶⁰ Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
⁶¹ Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁶² Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁶³ Division of Gastroenterology, Royal Victoria Hospital, Montréal, Québec, Canada.
⁶⁴ Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
⁶⁵ Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
⁶⁶ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada.
⁶⁷ Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.
⁶⁸ Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

PMID: 27503255
PMCID: PMC4980482
DOI: 10.1038/ncomms12342

Erratum in

Erratum: A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.
Rivas MA, Graham D, Sulem P, Stevens C, Desch AN, Goyette P, Gudbjartsson D, Jonsdottir I, Thorsteinsdottir U, Degenhardt F, Mucha S, Kurki MI, Li D, D'Amato M, Annese V, Vermeire S, Weersma RK, Halfvarson J, Paavola-Sakki P, Lappalainen M, Lek M, Cummings B, Tukiainen T, Haritunians T, Halme L, Koskinen LL, Ananthakrishnan AN, Luo Y, Heap GA, Visschedijk MC; UK IBD Genetics Consortium; NIDDK IBD Genetics Consortium; MacArthur DG, Neale BM, Ahmad T, Anderson CA, Brant SR, Duerr RH, Silverberg MS, Cho JH, Palotie A, Saavalainen P, Kontula K, Färkkilä M, McGovern DP, Franke A, Stefansson K, Rioux JD, Xavier RJ, Daly MJ. Rivas MA, et al. Nat Commun. 2016 Sep 13;7:12869. doi: 10.1038/ncomms12869. Nat Commun. 2016. PMID: 27619887 Free PMC article. No abstract available.

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.

PubMed Disclaimer

Conflict of interest statement

K.S. and his team report personal fees from deCODE Genetics/Amgen outside the submitted work. The remaining authors declare no competing financial interests.

Figures

**Figure 1. R179X impact on protein allele expression and cellular localization.**
(a) Schematic diagram of the RNF186 protein with a zinc finger RING-type and two helical transmembrane (TM1 and TM2) domains, and the A64T and R179X variants shown. (b) 293T cells were transfected with the indicated expression constructs and analysed by western blot for expression of Rnf186 and the R179X variant. The RNF186 protein with a premature stop at amino-acid position 179 is expressed, but at reduced levels. (c) 293T cells were transfected with the indicated expression constructs and analysed by immunofluorescence to demonstrate altered subcellular localization of the R179X variant.

See this image and copyright information in PMC

References

1. Jostins L. et al.. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012). - PMC - PubMed
1. Liu J. Z. et al.. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979–986 (2015). - PMC - PubMed
1. Gibson G. Rare and common variants: twenty arguments. Nat. Rev. Genet. 13, 135–145 (2011). - PMC - PubMed
1. MacArthur D. G. et al.. A systematic survey of loss-of-function variants in human protein-coding genes. Science 335, 823–828 (2012). - PMC - PubMed
1. Rivas M. A. et al.. Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome. Science 348, 666–669 (2015). - PMC - PubMed

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

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

Authors

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Erratum in

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Conflict of interest statement

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