Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

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Inherited determinants of Crohn's disease and ulcerative colitis phenotypes : a genetic association study

Cleynen, Isabelle (författare): Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK; Department of Clinical and Experimental Medicine TARGID, KU Leuven, Leuven, Belgium

Boucher, Gabrielle (författare): Montreal Heart Institute Research Center, Université de Montréal, Montréal, Canada

Jostins, Luke (författare): 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, UK

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Schumm, L. Philip (författare): Department of Public Health Sciences, University of Chicago, Chicago IL, USA

Zeissig, Sebastian (författare): Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany

Ahmad, Tariq (författare): Peninsula College of Medicine and Dentistry, Exeter, UK

Andersen, Vibeke (författare): Medical Department, Viborg Regional Hospital, Viborg, Denmark; Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark

Andrews, Jane M. (författare): Inflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia; School of Medicine, University of Adelaide, Adelaide, Australia

Annese, Vito (författare): 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, Italy

Brand, Stephan (författare): Department of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University, Munich, Germany

Brant, Steven R. (författare): 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, USA

Cho, Judy H. (författare): Department of Genetics, Yale School of Medicine, New Haven CT, USA

Daly, Mark J. (författare): Broad Institute of MIT and Harvard, Cambridge MA, USA

Dubinsky, Marla (författare): Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles CA, USA

Duerr, Richard H. (författare): 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, USA

Ferguson, Lynnette R. (författare): School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

Franke, Andre (författare): Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany

Gearry, Richard B. (författare): Department of Medicine, University of Otago, Christchurch, New Zealand; Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand

Goyette, Philippe (författare): Montreal Heart Institute, Research Center, Université de Montréal, Montréal, Canada

Hakonarson, Hakon (författare): Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia PA, USA

Halfvarson, Jonas, 1970- (författare): Örebro universitet,Institutionen för medicinska vetenskaper,Department of Gastroenterology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden

Hov, Johannes R. (författare): Norwegian PSC Research Center, Research Insitute of Internal Medicine and Department of Transplantation Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway

Huang, Hailang (författare): Broad Institute of MIT and Harvard, Cambridge MA, USA

Kennedy, Nicholas A. (författare): Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

Kupcinskas, Limas (författare): Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania

Lawrance, Ian C. (författare): 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, Australia

Lee, James C. (författare): Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK

Satsangi, Jack (författare): Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

Schreiber, Stephan (författare): Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany; Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark

Théâtre, Emilie (författare): 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, Belgium

van der Meulen-de Jong, Andrea E. (författare): Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands

Weersma, Rinse K. (författare): Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands

Wilson, David C. (författare): Child Life and Health, University of Edinburgh, Edinburgh, UK; Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Glasgow, UK

Parkes, Miles (författare): Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK

Vermeire, Severine (författare): Department of Clinical and Experimental Medicine TARGID, KU Leuven, Leuven, Belgium; Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium

Rioux, John D. (författare): Research Center, Université de Montréal, the Montreal Heart Institute, Montréal, Canada

Mansfield, John (författare): Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK

Silverberg, Mark S. (författare): Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto ON, Canada

Radford-Smith, Graham (författare): 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, Australia

McGovern, Dermot P. B. (författare): F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles CA, USA

Barrett, Jeffrey C. (författare): Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK

Lees, Charlie W. (författare): Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

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New York, USA : Elsevier, 2016
2016
Engelska.
Ingår i: The Lancet. - New York, USA : Elsevier. - 0140-6736 .- 1474-547X. ; 387:10014, s. 156-167

Relaterad länk:: https://doi.org/10.1...; visa fler...; https://urn.kb.se/re...; https://doi.org/10.1...; http://kipublication...; visa färre...

Tidskriftsartikel (refereegranskat)

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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).

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Av författaren/redakt...: Cleynen, Isabell ...; Boucher, Gabriel ...; Jostins, Luke; Schumm, L. Phili ...; Zeissig, Sebasti ...; Ahmad, Tariq; visa fler...; Andersen, Vibeke; Andrews, Jane M.; Annese, Vito; Brand, Stephan; Brant, Steven R.; Cho, Judy H.; Daly, Mark J.; Dubinsky, Marla; Duerr, Richard H ...; Ferguson, Lynnet ...; Franke, Andre; Gearry, Richard ...; Goyette, Philipp ...; Hakonarson, Hako ...; Halfvarson, Jona ...; Hov, Johannes R.; Huang, Hailang; Kennedy, Nichola ...; Kupcinskas, Lima ...; Lawrance, Ian C.; Lee, James C.; Satsangi, Jack; Schreiber, Steph ...; Théâtre, Emilie; van der Meulen-d ...; Weersma, Rinse K ...; Wilson, David C.; Parkes, Miles; Vermeire, Severi ...; Rioux, John D.; Mansfield, John; Silverberg, Mark ...; Radford-Smith, G ...; McGovern, Dermot ...; Barrett, Jeffrey ...; Lees, Charlie W.; visa färre...

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Gastroenterologi

Artiklar i publikationen: The Lancet

Av lärosätet: Örebro universitet; Karolinska Institutet

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Inherited determinants of Crohn's disease and ulcerative colitis phenotypes : a genetic association study

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