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

      research-article

      , PhD a , b , * , , MSc c , * , , PhD a , d , e , * , , MA f , , PhD g , , PhD j , , Prof, PhD k , l , , Prof, MD m , n , , MD o , p , , Prof, MD q , , MD r , s , , Prof, MD t , , Prof, PhD u , , MD v , , Prof, MD w , x , , Prof, PhD y , , Prof, PhD h , , Prof, PhD z , aa , , PhD c , , Prof, PhD ab , , MD ac , ad , , PhD ae , , PhD u , , PhD af , , Prof, MD ah , , Prof, PhD ai , , PhD aj , , Prof, FRSE af , , Prof, PhD h , i , , PhD ak , al , , MD am , , Prof, PhD an , , Prof, PhD ag , ao , International Inflammatory Bowel Disease Genetics Consortium , , PhD aj , , Prof, PhD b , ap , , Prof, PhD c , , MD aq , , PhD ar , , PhD as , at , , Prof, PhD au , * , , Dr, PhD a , * , ** , , Dr, PhD af , * , *

      Lancet (London, England)

      Elsevier

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          Summary

          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).

          Related collections

          Most cited references 29

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          Infliximab for induction and maintenance therapy for ulcerative colitis.

          Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor alpha, is an established treatment for Crohn's disease but not ulcerative colitis. Two randomized, double-blind, placebo-controlled studies--the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively)--evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0.001 for both comparisons with placebo). A response was defined as a decrease in the Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal-bleeding subscore of 0 or 1. In ACT 2, 64 percent of patients who received 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical response at week 8, as compared with 29 percent of those who received placebo (P<0.001 for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (P< or =0.002 for all comparisons). In ACT 1, more patients who received 5 mg or 10 mg of infliximab had a clinical response at week 54 (45 percent and 44 percent, respectively) than did those who received placebo (20 percent, P<0.001 for both comparisons). Patients with moderate-to-severe active ulcerative colitis treated with infliximab at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo. (ClinicalTrials.gov numbers, NCT00036439 and NCT00096655.) Copyright 2005 Massachusetts Medical Society.
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            • Article: not found

            Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial.

            Tumor necrosis factor blockade has been shown to be an effective treatment strategy in Crohn's disease (CD). Adalimumab is a human immunoglobulin G1 (IgG(1)) monoclonal antibody targeting tumor necrosis factor (TNF). A randomized, double-blind, placebo-controlled, dose-ranging trial was performed to evaluate the efficacy of adalimumab induction therapy in patients with CD. A total of 299 patients with moderate to severe CD naive to anti-TNF therapy were randomized to receive subcutaneous injections at weeks 0 and 2 with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg or placebo. The primary endpoint was demonstration of a significant difference in the rates of remission at week 4 (defined as a Crohn's Disease Activity Index score <150 points) among the 80 mg/40 mg, 160 mg/80 mg, and placebo groups. The rates of remission at week 4 in the adalimumab 40 mg/20 mg, 80 mg/40 mg, and 160 mg/80 mg groups were 18% (P = .36), 24% (P = .06), and 36% (P = .001), respectively, and 12% in the placebo group. Adverse events occurred at similar frequencies in all 4 treatment groups except injection site reactions, which were more common in adalimumab-treated patients. Adalimumab was superior to placebo for induction of remission in patients with moderate to severe Crohn's disease naive to anti-TNF therapy. The optimal induction dosing regimen for adalimumab in this study was 160 mg at week 0 followed by 80 mg at week 2. Adalimumab was well tolerated.
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              Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.

              Adalimumab is a fully human monoclonal antibody that binds tumor necrosis factor (TNF)-α. Its efficacy as maintenance therapy for patients with ulcerative colitis has not been studied in a controlled, double-blind trial. Ulcerative colitis long-term remission and maintenance with adalimumab 2 (ULTRA 2) was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of adalimumab in induction and maintenance of clinical remission in 494 patients with moderate-to-severe ulcerative colitis who received concurrent treatment with oral corticosteroids or immunosuppressants. Patients were stratified based on prior exposure to TNF-α antagonists (either had or had not been previously treated with anti-TNF-α) and randomly assigned to groups given adalimumab 160 mg at week 0, 80 mg at week 2, and then 40 mg every other week or placebo. Primary end points were remission at weeks 8 and 52. Overall rates of clinical remission at week 8 were 16.5% on adalimumab and 9.3% on placebo (P = .019); corresponding values for week 52 were 17.3% and 8.5% (P = .004). Among anti-TNF-α naïve patients, rates of remission at week 8 were 21.3% on adalimumab and 11% on placebo (P = .017); corresponding values for week 52 were 22% and 12.4% (P = .029). Among patients who had previously received anti-TNF agents, rates of remission at week 8 were 9.2% on adalimumab and 6.9% on placebo (P = .559); corresponding values for week 52 were 10.2% and 3% (P = .039). Serious adverse events occurred in 12% of patients given adalimumab or placebo. Serious infections developed in 1.6% of patients given adalimumab and 1.9% given placebo. In the group given adalimumab, 1 patient developed squamous cell carcinoma and 1 developed gastric cancer. Adalimumab was safe and more effective than placebo in inducing and maintaining clinical remission in patients with moderate-to-severe ulcerative colitis who did not have an adequate response to conventional therapy with steroids or immunosuppressants. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Lancet
                Lancet
                Lancet (London, England)
                Elsevier
                0140-6736
                1474-547X
                09 January 2016
                09 January 2016
                : 387
                : 10014
                : 156-167
                Affiliations
                [a ]Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
                [b ]Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium
                [c ]Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada
                [d ]Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
                [e ]Christ Church, University of Oxford, St Aldates, UK
                [f ]Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
                [g ]Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
                [h ]Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
                [i ]Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
                [j ]Peninsula College of Medicine and Dentistry, Exeter, UK
                [k ]Medical Department, Viborg Regional Hospital, Viborg, Denmark
                [l ]Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark
                [m ]Inflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
                [n ]School of Medicine, University of Adelaide, Adelaide, Australia
                [o ]Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo, Italy
                [p ]Azienda Ospedaliero Universitaria (AOU) Careggi, Unit of Gastroenterology SOD2, Florence, Italy
                [q ]Department of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University, Munich, Germany
                [r ]Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
                [s ]Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
                [t ]Department of Genetics, Yale School of Medicine, New Haven, CT, USA
                [u ]Broad Institute of MIT and Harvard, Cambridge, MA, USA
                [v ]Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, CA, USA
                [w ]Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
                [x ]Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA
                [y ]School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
                [z ]Department of Medicine, University of Otago, Christchurch, New Zealand
                [aa ]Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
                [ab ]Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
                [ac ]Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Sweden
                [ad ]School of Health and Medical Sciences, Örebro University, Örebro, Sweden
                [ae ]Norwegian PSC Research Center, Research Insitute of Internal Medicine and Department of Transplantation Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
                [af ]Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
                [ag ]Child Life and Health, University of Edinburgh, Edinburgh, UK
                [ah ]Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
                [ai ]Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Subiaco WA and School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute for Medical Research, Murdoch, WA, Australia
                [aj ]Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
                [ak ]Unit of Animal Genomics, Groupe Interdisciplinaire de Genoproteomique Appliquee (GIGA-R) and Faculty of Veterinary Medicine, University of Liege, Liege, Belgium
                [al ]Division of Gastroenterology, Centre Hospitalier Universitaire, Universite de Liege, Liege, Belgium
                [am ]Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands
                [an ]Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
                [ao ]Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Glasgow, UK
                [ap ]Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
                [aq ]Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK
                [ar ]Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, ON, Canada
                [as ]Inflammatory Bowel Diseases, Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia
                [at ]Department of Gastroenterology, Royal Brisbane and Women's Hospital, and School of Medicine, University of Queensland, Brisbane, Australia
                [au ]F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
                Author notes
                [* ]Correspondence to: Dr Charlie W Lees, Gastrointestinal Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UKCorrespondence to: Dr Charlie W LeesGastrointestinal UnitWestern General HospitalCrewe RoadEdinburghEH4 2XUUK Charlie.lees@ 123456ed.ac.uk
                [** ]Dr Jeffrey C Barrett, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UKDr Jeffrey C BarrettWellcome Trust Sanger InstituteHinxtonCambridgeshireCB10 1SAUK barrett@ 123456sanger.ac.uk
                [*]

                Contributed equally

                [†]

                See appendix A for full list of investigators

                Article
                S0140-6736(15)00465-1
                10.1016/S0140-6736(15)00465-1
                4714968
                26490195
                © 2016 Cleynen et al. Open Access article distributed under the terms of CC BY

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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