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FältnamnIndikatorerMetadata
00011950naa a2200817 4500
001oai:DiVA.org:oru-54453
003SwePub
008170111s2016 | |||||||||||000 ||eng|
009oai:prod.swepub.kib.ki.se:132784845
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-544532 URI
0247 a https://doi.org/10.1016/S0140-6736(15)00465-12 DOI
0247 a http://kipublications.ki.se/Default.aspx?queryparsed=id:1327848452 URI
040 a (SwePub)orud (SwePub)ki
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Cleynen, Isabelleu Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK; Department of Clinical and Experimental Medicine TARGID, KU Leuven, Leuven, Belgium4 aut
2451 0a Inherited determinants of Crohn's disease and ulcerative colitis phenotypes :b a genetic association study
264 1a New York, USA :b Elsevier,c 2016
338 a print2 rdacarrier
520 a Background: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile.Findings: After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)).Interpretation: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time.Funding: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).
650 7a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Gastroenterologi0 (SwePub)302132 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Gastroenterology and Hepatology0 (SwePub)302132 hsv//eng
7001 a Boucher, Gabrielleu Montreal Heart Institute Research Center, Université de Montréal, Montréal, Canada4 aut
7001 a Jostins, Lukeu Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Christ Church, University of Oxford, St Aldates, UK4 aut
7001 a Schumm, L. Philipu Department of Public Health Sciences, University of Chicago, Chicago IL, USA4 aut
7001 a Zeissig, Sebastianu Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany4 aut
7001 a Ahmad, Tariqu Peninsula College of Medicine and Dentistry, Exeter, UK4 aut
7001 a Andersen, Vibekeu Medical Department, Viborg Regional Hospital, Viborg, Denmark; Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark4 aut
7001 a Andrews, Jane M.u Inflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia; School of Medicine, University of Adelaide, Adelaide, Australia4 aut
7001 a Annese, Vitou Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo, Italy; Unit of Gastroenterology SOD2, Azienda Ospedaliero Universitaria (AOU) Careggi, Florence, Italy4 aut
7001 a Brand, Stephanu Department of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University, Munich, Germany4 aut
7001 a Brant, Steven R.u Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore MD, USA; Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore MD, USA4 aut
7001 a Cho, Judy H.u Department of Genetics, Yale School of Medicine, New Haven CT, USA4 aut
7001 a Daly, Mark J.u Broad Institute of MIT and Harvard, Cambridge MA, USA4 aut
7001 a Dubinsky, Marlau Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles CA, USA4 aut
7001 a Duerr, Richard H.u Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh PA, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh PA, USA4 aut
7001 a Ferguson, Lynnette R.u School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand4 aut
7001 a Franke, Andreu Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany4 aut
7001 a Gearry, Richard B.u Department of Medicine, University of Otago, Christchurch, New Zealand; Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand4 aut
7001 a Goyette, Philippeu Montreal Heart Institute, Research Center, Université de Montréal, Montréal, Canada4 aut
7001 a Hakonarson, Hakonu Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia PA, USA4 aut
7001 a Halfvarson, Jonas,d 1970-u Örebro universitet,Institutionen för medicinska vetenskaper,Department of Gastroenterology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden4 aut0 (Swepub:oru)jshn
7001 a Hov, Johannes R.u Norwegian PSC Research Center, Research Insitute of Internal Medicine and Department of Transplantation Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway4 aut
7001 a Huang, Hailangu Broad Institute of MIT and Harvard, Cambridge MA, USA4 aut
7001 a Kennedy, Nicholas A.u Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK4 aut
7001 a Kupcinskas, Limasu Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania4 aut
7001 a Lawrance, Ian C.u Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Perth WA, Australia; Harry Perkins Institute for Medical Research, School of Medicine and Pharmacology, University of Western Australia, Murdoch WA, Australia4 aut
7001 a Lee, James C.u Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK4 aut
7001 a Satsangi, Jacku Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK4 aut
7001 a Schreiber, Stephanu Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany; Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark4 aut
7001 a Théâtre, Emilieu Unit of Animal Genomics, Groupe Interdisciplinaire de Genoproteomique Appliquee (GIGA-R) and Faculty of Veterinary Medicine, University of Liege, Liege, Belgium; Division of Gastroenterology, Centre Hospitalier Universitaire, Universite de Liege, Liege, Belgium4 aut
7001 a van der Meulen-de Jong, Andrea E.u Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands4 aut
7001 a Weersma, Rinse K.u Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands4 aut
7001 a Wilson, David C.u Child Life and Health, University of Edinburgh, Edinburgh, UK; Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Glasgow, UK4 aut
7001 a Parkes, Milesu Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK4 aut
7001 a Vermeire, Severineu Department of Clinical and Experimental Medicine TARGID, KU Leuven, Leuven, Belgium; Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium4 aut
7001 a Rioux, John D.u Research Center, Université de Montréal, the Montreal Heart Institute, Montréal, Canada4 aut
7001 a Mansfield, Johnu Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK4 aut
7001 a Silverberg, Mark S.u Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto ON, Canada4 aut
7001 a Radford-Smith, Grahamu Inflammatory Bowel Diseases, Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia; Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Australia; School of Medicine, University of Queensland, Brisbane, Australia4 aut
7001 a McGovern, Dermot P. B.u F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles CA, USA4 aut
7001 a Barrett, Jeffrey C.u Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK4 aut
7001 a Lees, Charlie W.u Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK4 aut
7102 a Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK; Department of Clinical and Experimental Medicine TARGID, KU Leuven, Leuven, Belgiumb Montreal Heart Institute Research Center, Université de Montréal, Montréal, Canada4 org
7730 t The Lancetd New York, USA : Elsevierg 387:10014, s. 156-167q 387:10014<156-167x 0140-6736x 1474-547X
8564 u https://doi.org/10.1016/S0140-6736(15)00465-1y Fulltext
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-54453
8564 8u https://doi.org/10.1016/S0140-6736(15)00465-1
8564 8u http://kipublications.ki.se/Default.aspx?queryparsed=id:132784845

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