Evidence map›Paper›PMID 26490195›Full record

ArticleLancet (London, England)2016

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

Isabelle Cleynen, Gabrielle Boucher, Luke Jostins, L Philip Schumm, Sebastian Zeissig, Tariq Ahmad, Vibeke Andersen, Jane M Andrews, Vito Annese, Stephan Brand and 33 more

Registry-linked trialAbstract readMulticenter Study
PubMed Full text at PMC Publisher
In one paragraph

Article in Lancet (London, England), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02796339 (A Phase-II Clinical Trial on the Effectiveness of a Nutritional Supplement With Natural Mastiha in Inflammatory Bowel Diseases Patients.), which is not on this map. Cited by 389 papers, 5 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
389citing papers in PubMed, 5 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT02796339 phase2completednot on this map

A Phase-II Clinical Trial on the Effectiveness of a Nutritional Supplement With Natural Mastiha in Inflammatory Bowel Diseases Patients.

TypeinterventionalSponsorHarokopio UniversityRan2016 to 2021Enrolled100ConditionsInflammatory Bowel DiseasesArmsMastiha, Placebo
3 · Its place in the literature

Who cites it

389 citing papers in PubMed, 5 syntheses or guidelines pooled it.

  1. Pooled it
  2. Short-chain fatty acids in the treatment of ulcerative colitis. Systematic review and meta-analysis.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2025
    Pooled it
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  20. New approach methodologies in Crohn's disease link molecular disease subtypes to clinical outcomes.American journal of physiology. Gastrointestinal and liver physiology · 2026
    Article

329 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

43 authors.

Isabelle CleynenWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium.
Gabrielle BoucherUniversité de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada.
Luke JostinsWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Christ Church, University of Oxford, St Aldates, UK.
L Philip SchummDepartment of Public Health Sciences, University of Chicago, Chicago, IL, USA.
Sebastian ZeissigDepartment for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany.
Tariq AhmadPeninsula College of Medicine and Dentistry, Exeter, UK.
Vibeke AndersenMedical Department, Viborg Regional Hospital, Viborg, Denmark; Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark.
Jane M AndrewsInflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia; School of Medicine, University of Adelaide, Adelaide, Australia.
Vito AnneseUnit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo, Italy; Azienda Ospedaliero Universitaria (AOU) Careggi, Unit of Gastroenterology SOD2, Florence, Italy.
Stephan BrandDepartment of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Steven R BrantMeyerhoff 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.
Judy H ChoDepartment of Genetics, Yale School of Medicine, New Haven, CT, USA.
Mark J DalyBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Marla DubinskyDepartment of Pediatrics, Cedars Sinai Medical Center, Los Angeles, CA, USA.
Richard H DuerrDivision 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.
Lynnette R FergusonSchool of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Andre FrankeInstitute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
Richard B GearryDepartment of Medicine, University of Otago, Christchurch, New Zealand; Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand.
Philippe GoyetteUniversité de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada.
Hakon HakonarsonCenter for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Jonas HalfvarsonDepartment of Gastroenterology, Faculty of Medicine and Health, Örebro University, Sweden; School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
Johannes R HovNorwegian PSC Research Center, Research Insitute of Internal Medicine and Department of Transplantation Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway.
Hailang HuangBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Nicholas A KennedyGastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Limas KupcinskasDepartment of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Ian C LawranceCentre 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.
James C LeeInflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
Jack SatsangiGastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Stephan SchreiberInstitute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany; Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany.
Emilie ThéâtreUnit 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.
Andrea E van der Meulen-de JongDepartment of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands.
Rinse K WeersmaDepartment of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands.
David C WilsonChild Life and Health, University of Edinburgh, Edinburgh, UK; Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Glasgow, UK.
International Inflammatory Bowel Disease Genetics Consortium
Miles ParkesInflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
Severine VermeireDepartment of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium; Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.
John D RiouxUniversité de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada.
John MansfieldInstitute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
Mark S SilverbergMount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, ON, Canada.
Graham Radford-SmithInflammatory Bowel Diseases, Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia; Department of Gastroenterology, Royal Brisbane and Women's Hospital, and School of Medicine, University of Queensland, Brisbane, Australia.
Dermot P B McGovernF Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Jeffrey C BarrettWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. Electronic address: barrett@sanger.ac.uk.
Charlie W LeesGastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. Electronic address: Charlie.lees@ed.ac.uk.

Funding

Yale Pathology Tissue Services Shared ResourceP30CA016359 · NCI · YALE UNIVERSITY · PI DAVID L RIMM · 1985 to 2026
$85.0M
Type 1 Diabetes Genetics ConsortiumU01DK062418 · NIDDK · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI RICH, STEPHEN S. · 2002 to 2007
$59.8M
Pilot & Feasibility ProgramP30DK043351 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI RAYMOND T CHUNG · 1991 to 2026
$35.3M
Using polygenic scores to enhance both variant discovery, and understanding of functional consequences of genetic variation in IBD.P01DK046763 · NIDDK · CEDARS-SINAI MEDICAL CENTER · PI TARGAN, STEPHAN R. · 1992 to 2020
$31.1M
Inflammatory Bowel Disease Genetics Consortium Data Coordinating CenterU01DK062429 · NIDDK · YALE UNIVERSITY · PI CHO, JUDY H. · 2002 to 2016
$16.8M
Precision IBD via genetics and genomics: integrating International and multi-omic datasets, expanding studies in diverse populations, and defining mechanisms of unmet clinical needs in IBDU24DK062429 · NIDDK · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Ling-shiang Chuang, Ron Do · 2017 to 2026
$13.9M
Utilizing the Phenomics of IBD to Enhance Gene DiscoveryU01DK062413 · NIDDK · CEDARS-SINAI MEDICAL CENTER · PI Dermot Patrick McGovern · 2002 to 2026
$12.2M
Translational Research Enhancement CoreP30DK089502 · NIDDK · JOHNS HOPKINS UNIVERSITY · PI ZACHOS, NICHOLAS CONSTANTINE · 2011 to 2020
$12.0M
The Role of HLA and KIR in Rheumatoid Arthritis and Crohn's DiseaseU01AI067068 · NIAID · STANFORD UNIVERSITY · PI ERLICH, HENRY A, TRACHTENBERG, ELIZABETH A · 2005 to 2014
$10.9M
Yale University Inflammatory Bowel Disease Genetics Research CenterU01DK062422 · NIDDK · YALE UNIVERSITY · PI Ling-shiang Chuang · 2002 to 2026
$10.8M
IBD Gene Mapping by Clinical and Population SubsetsU01DK062431 · NIDDK · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · PI Steven R Brant · 2002 to 2026
$10.7M
Universite de Montreal IBD Genetics Research CenterU01DK062432 · NIDDK · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · PI John D. Rioux · 2002 to 2026
$9.6M
AHRQ HHS HS021747AHRQ HHS R01 HS021747Chief Scientist Office ETM/137Chief Scientist Office ETM/75Medical Research Council G0600329Medical Research Council G0800675Medical Research Council G0800759MRF_ C0482NCI NIH HHS P30 CA016359NCI NIH HHS R01 CA141743NIAID NIH HHS AI067068NIAID NIH HHS U01 AI067068NIDCR NIH HHS U54 DE023789NIDCR NIH HHS U54DE023789-01NIDDK NIH HHS DK062413NIDDK NIH HHS DK062420NIDDK NIH HHS DK062422NIDDK NIH HHS DK062423NIDDK NIH HHS DK062429NIDDK NIH HHS DK062429-S1NIDDK NIH HHS DK062431NIDDK NIH HHS DK062432NIDDK NIH HHS DK076984NIDDK NIH HHS DK084554NIDDK NIH HHS P01 DK046763NIDDK NIH HHS P01DK046763NIDDK NIH HHS P30 DK043351NIDDK NIH HHS P30 DK089502NIDDK NIH HHS R03 DK076984NIDDK NIH HHS R21 DK084554NIDDK NIH HHS U01 DK062413NIDDK NIH HHS U01 DK062418NIDDK NIH HHS U01 DK062420NIDDK NIH HHS U01 DK062422NIDDK NIH HHS U01 DK062423NIDDK NIH HHS U01 DK062429NIDDK NIH HHS U01 DK062431NIDDK NIH HHS U01 DK062432NIDDK NIH HHS U24 DK062429Wellcome TrustWellcome Trust 083948/Z/07/ZWellcome Trust 085475/B/08/ZWellcome Trust 085475/Z/08/ZWellcome Trust 098051Wellcome Trust 098759
6 · The paper itself

Abstract

backgroundCrohn'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.

methodsThis 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.

findingsAfter 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)).

interpretationOur 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.

fundingInternational Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).

Indexed as

Genetic Association StudiesGenetic Predisposition to DiseaseAdultAllelesColitis, UlcerativeCrohn DiseaseFemaleGenotypeHepatocyte Growth FactorHLA-DRB1 ChainsHumansImmunoassayMajor Histocompatibility ComplexMaleNod2 Signaling Adaptor ProteinPhenotypeHepatocyte Growth FactorHLA-DRB1 Chainsmacrophage stimulating proteinNOD2 protein, humanNod2 Signaling Adaptor ProteinProto-Oncogene Proteins

Identifiers

PMID26490195
PMCPMC4714968

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