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

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... Full description

Journal Title: The Lancet (British edition) 2016, Vol.387 (10014), p.156-167
Main Author: Cleynen, Isabelle, PhD
Other Authors: Boucher, Gabrielle, MSc , Jostins, Luke, PhD , Schumm, L Philip, MA , Zeissig, Sebastian, PhD , Ahmad, Tariq, PhD , Andersen, Vibeke, Prof , Andrews, Jane M, Prof , Annese, Vito, MD , Brand, Stephan, Prof , Brant, Steven R, MD , Cho, Judy H, Prof , Daly, Mark J, Prof , Dubinsky, Marla, MD , Duerr, Richard H, Prof , Ferguson, Lynnette R, Prof , Franke, Andre, Prof , Gearry, Richard B, Prof , Goyette, Philippe, PhD , Hakonarson, Hakon, Prof , Halfvarson, Jonas, MD , Hov, Johannes R, PhD , Huang, Hailang, PhD , Kennedy, Nicholas A, PhD , Kupcinskas, Limas, Prof , Lawrance, Ian C, Prof , Lee, James C, PhD , Satsangi, Jack, Prof , Schreiber, Stephan, Prof , Théâtre, Emilie, PhD , van der Meulen-de Jong, Andrea E, MD , Weersma, Rinse K, Prof , Wilson, David C, Prof , Parkes, Miles, PhD , Vermeire, Severine, Prof , Rioux, John D, Prof , Mansfield, John, MD , Silverberg, Mark S, PhD , Radford-Smith, Graham, PhD , McGovern, Dermot P B, Prof , Barrett, Jeffrey C, Dr , Lees, Charlie W, Dr
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: England: Elsevier Ltd
ID: ISSN: 0140-6736
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title: Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study
format: Article
creator:
  • Cleynen, Isabelle, PhD
  • Boucher, Gabrielle, MSc
  • Jostins, Luke, PhD
  • Schumm, L Philip, MA
  • Zeissig, Sebastian, PhD
  • Ahmad, Tariq, PhD
  • Andersen, Vibeke, Prof
  • Andrews, Jane M, Prof
  • Annese, Vito, MD
  • Brand, Stephan, Prof
  • Brant, Steven R, MD
  • Cho, Judy H, Prof
  • Daly, Mark J, Prof
  • Dubinsky, Marla, MD
  • Duerr, Richard H, Prof
  • Ferguson, Lynnette R, Prof
  • Franke, Andre, Prof
  • Gearry, Richard B, Prof
  • Goyette, Philippe, PhD
  • Hakonarson, Hakon, Prof
  • Halfvarson, Jonas, MD
  • Hov, Johannes R, PhD
  • Huang, Hailang, PhD
  • Kennedy, Nicholas A, PhD
  • Kupcinskas, Limas, Prof
  • Lawrance, Ian C, Prof
  • Lee, James C, PhD
  • Satsangi, Jack, Prof
  • Schreiber, Stephan, Prof
  • Théâtre, Emilie, PhD
  • van der Meulen-de Jong, Andrea E, MD
  • Weersma, Rinse K, Prof
  • Wilson, David C, Prof
  • Parkes, Miles, PhD
  • Vermeire, Severine, Prof
  • Rioux, John D, Prof
  • Mansfield, John, MD
  • Silverberg, Mark S, PhD
  • Radford-Smith, Graham, PhD
  • McGovern, Dermot P B, Prof
  • Barrett, Jeffrey C, Dr
  • Lees, Charlie W, Dr
subjects:
  • Adult
  • Alleles
  • Clinical Medicine
  • Colitis
  • Colitis, Ulcerative - genetics
  • Colon
  • Crohn Disease - genetics
  • Crohns disease
  • Family medical history
  • Female
  • Gastroenterologi
  • Gastroenterology & hepatology
  • Gastroenterology and Hepatology
  • Gastroentérologie & hépatologie
  • Genetic aspects
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genetic research
  • Genetics
  • Genotype
  • Genotype & phenotype
  • Hepatocyte Growth Factor - genetics
  • HLA-DRB1 Chains - genetics
  • Human health sciences
  • Humans
  • Immunoassay
  • Inflammatory bowel disease
  • Internal Medicine
  • Klinisk medicin
  • Major Histocompatibility Complex - genetics
  • Male
  • Medical and Health Sciences
  • Medical research
  • Medicin och hälsovetenskap
  • Medicine, Experimental
  • Nod2 Signaling Adaptor Protein - genetics
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins - genetics
  • Risk Assessment
  • Sciences de la santé humaine
  • Young Adult
ispartof: The Lancet (British edition), 2016, Vol.387 (10014), p.156-167
description: 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 d
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0140-6736
fulltext: fulltext
issn:
  • 0140-6736
  • 1474-547X
  • 1474-547X
url: Link


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titleInherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study
sourceAlma/SFX Local Collection
creatorCleynen, Isabelle, PhD ; Boucher, Gabrielle, MSc ; Jostins, Luke, PhD ; Schumm, L Philip, MA ; Zeissig, Sebastian, PhD ; Ahmad, Tariq, PhD ; Andersen, Vibeke, Prof ; Andrews, Jane M, Prof ; Annese, Vito, MD ; Brand, Stephan, Prof ; Brant, Steven R, MD ; Cho, Judy H, Prof ; Daly, Mark J, Prof ; Dubinsky, Marla, MD ; Duerr, Richard H, Prof ; Ferguson, Lynnette R, Prof ; Franke, Andre, Prof ; Gearry, Richard B, Prof ; Goyette, Philippe, PhD ; Hakonarson, Hakon, Prof ; Halfvarson, Jonas, MD ; Hov, Johannes R, PhD ; Huang, Hailang, PhD ; Kennedy, Nicholas A, PhD ; Kupcinskas, Limas, Prof ; Lawrance, Ian C, Prof ; Lee, James C, PhD ; Satsangi, Jack, Prof ; Schreiber, Stephan, Prof ; Théâtre, Emilie, PhD ; van der Meulen-de Jong, Andrea E, MD ; Weersma, Rinse K, Prof ; Wilson, David C, Prof ; Parkes, Miles, PhD ; Vermeire, Severine, Prof ; Rioux, John D, Prof ; Mansfield, John, MD ; Silverberg, Mark S, PhD ; Radford-Smith, Graham, PhD ; McGovern, Dermot P B, Prof ; Barrett, Jeffrey C, Dr ; Lees, Charlie W, Dr
creatorcontribCleynen, Isabelle, PhD ; Boucher, Gabrielle, MSc ; Jostins, Luke, PhD ; Schumm, L Philip, MA ; Zeissig, Sebastian, PhD ; Ahmad, Tariq, PhD ; Andersen, Vibeke, Prof ; Andrews, Jane M, Prof ; Annese, Vito, MD ; Brand, Stephan, Prof ; Brant, Steven R, MD ; Cho, Judy H, Prof ; Daly, Mark J, Prof ; Dubinsky, Marla, MD ; Duerr, Richard H, Prof ; Ferguson, Lynnette R, Prof ; Franke, Andre, Prof ; Gearry, Richard B, Prof ; Goyette, Philippe, PhD ; Hakonarson, Hakon, Prof ; Halfvarson, Jonas, MD ; Hov, Johannes R, PhD ; Huang, Hailang, PhD ; Kennedy, Nicholas A, PhD ; Kupcinskas, Limas, Prof ; Lawrance, Ian C, Prof ; Lee, James C, PhD ; Satsangi, Jack, Prof ; Schreiber, Stephan, Prof ; Théâtre, Emilie, PhD ; van der Meulen-de Jong, Andrea E, MD ; Weersma, Rinse K, Prof ; Wilson, David C, Prof ; Parkes, Miles, PhD ; Vermeire, Severine, Prof ; Rioux, John D, Prof ; Mansfield, John, MD ; Silverberg, Mark S, PhD ; Radford-Smith, Graham, PhD ; McGovern, Dermot P B, Prof ; Barrett, Jeffrey C, Dr ; Lees, Charlie W, Dr ; International Inflammatory Bowel Disease Genetics Consortium
descriptionSummary 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).
identifier
0ISSN: 0140-6736
1ISSN: 1474-547X
2EISSN: 1474-547X
3DOI: 10.1016/S0140-6736(15)00465-1
4PMID: 26490195
5CODEN: LANCAO
languageeng
publisherEngland: Elsevier Ltd
subjectAdult ; Alleles ; Clinical Medicine ; Colitis ; Colitis, Ulcerative - genetics ; Colon ; Crohn Disease - genetics ; Crohns disease ; Family medical history ; Female ; Gastroenterologi ; Gastroenterology & hepatology ; Gastroenterology and Hepatology ; Gastroentérologie & hépatologie ; Genetic aspects ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genetic research ; Genetics ; Genotype ; Genotype & phenotype ; Hepatocyte Growth Factor - genetics ; HLA-DRB1 Chains - genetics ; Human health sciences ; Humans ; Immunoassay ; Inflammatory bowel disease ; Internal Medicine ; Klinisk medicin ; Major Histocompatibility Complex - genetics ; Male ; Medical and Health Sciences ; Medical research ; Medicin och hälsovetenskap ; Medicine, Experimental ; Nod2 Signaling Adaptor Protein - genetics ; Phenotype ; Polymorphism, Single Nucleotide ; Proto-Oncogene Proteins - genetics ; Risk Assessment ; Sciences de la santé humaine ; Young Adult
ispartofThe Lancet (British edition), 2016, Vol.387 (10014), p.156-167
rights
0Cleynen et al. Open Access article distributed under the terms of CC BY
12016 Cleynen et al. Open Access article distributed under the terms of CC BY
2Copyright © 2016 Cleynen et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.
3COPYRIGHT 2016 Elsevier B.V.
4Copyright Elsevier Limited Jan 9, 2016
52016 Cleynen et al. Open Access article distributed under the terms of CC BY 2016
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0Cleynen, Isabelle, PhD
1Boucher, Gabrielle, MSc
2Jostins, Luke, PhD
3Schumm, L Philip, MA
4Zeissig, Sebastian, PhD
5Ahmad, Tariq, PhD
6Andersen, Vibeke, Prof
7Andrews, Jane M, Prof
8Annese, Vito, MD
9Brand, Stephan, Prof
10Brant, Steven R, MD
11Cho, Judy H, Prof
12Daly, Mark J, Prof
13Dubinsky, Marla, MD
14Duerr, Richard H, Prof
15Ferguson, Lynnette R, Prof
16Franke, Andre, Prof
17Gearry, Richard B, Prof
18Goyette, Philippe, PhD
19Hakonarson, Hakon, Prof
20Halfvarson, Jonas, MD
21Hov, Johannes R, PhD
22Huang, Hailang, PhD
23Kennedy, Nicholas A, PhD
24Kupcinskas, Limas, Prof
25Lawrance, Ian C, Prof
26Lee, James C, PhD
27Satsangi, Jack, Prof
28Schreiber, Stephan, Prof
29Théâtre, Emilie, PhD
30van der Meulen-de Jong, Andrea E, MD
31Weersma, Rinse K, Prof
32Wilson, David C, Prof
33Parkes, Miles, PhD
34Vermeire, Severine, Prof
35Rioux, John D, Prof
36Mansfield, John, MD
37Silverberg, Mark S, PhD
38Radford-Smith, Graham, PhD
39McGovern, Dermot P B, Prof
40Barrett, Jeffrey C, Dr
41Lees, Charlie W, Dr
42International Inflammatory Bowel Disease Genetics Consortium
title
0Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study
1The Lancet (British edition)
addtitleLancet
descriptionSummary 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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1Alleles
2Clinical Medicine
3Colitis
4Colitis, Ulcerative - genetics
5Colon
6Crohn Disease - genetics
7Crohns disease
8Family medical history
9Female
10Gastroenterologi
11Gastroenterology & hepatology
12Gastroenterology and Hepatology
13Gastroentérologie & hépatologie
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15Genetic Association Studies
16Genetic Predisposition to Disease
17Genetic research
18Genetics
19Genotype
20Genotype & phenotype
21Hepatocyte Growth Factor - genetics
22HLA-DRB1 Chains - genetics
23Human health sciences
24Humans
25Immunoassay
26Inflammatory bowel disease
27Internal Medicine
28Klinisk medicin
29Major Histocompatibility Complex - genetics
30Male
31Medical and Health Sciences
32Medical research
33Medicin och hälsovetenskap
34Medicine, Experimental
35Nod2 Signaling Adaptor Protein - genetics
36Phenotype
37Polymorphism, Single Nucleotide
38Proto-Oncogene Proteins - genetics
39Risk Assessment
40Sciences de la santé humaine
41Young Adult
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11Cho, Judy H, Prof
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13Dubinsky, Marla, MD
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15Ferguson, Lynnette R, Prof
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17Gearry, Richard B, Prof
18Goyette, Philippe, PhD
19Hakonarson, Hakon, Prof
20Halfvarson, Jonas, MD
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22Huang, Hailang, PhD
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30van der Meulen-de Jong, Andrea E, MD
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33Parkes, Miles, PhD
34Vermeire, Severine, Prof
35Rioux, John D, Prof
36Mansfield, John, MD
37Silverberg, Mark S, PhD
38Radford-Smith, Graham, PhD
39McGovern, Dermot P B, Prof
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creationdate2016
titleInherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study
authorCleynen, Isabelle, PhD ; Boucher, Gabrielle, MSc ; Jostins, Luke, PhD ; Schumm, L Philip, MA ; Zeissig, Sebastian, PhD ; Ahmad, Tariq, PhD ; Andersen, Vibeke, Prof ; Andrews, Jane M, Prof ; Annese, Vito, MD ; Brand, Stephan, Prof ; Brant, Steven R, MD ; Cho, Judy H, Prof ; Daly, Mark J, Prof ; Dubinsky, Marla, MD ; Duerr, Richard H, Prof ; Ferguson, Lynnette R, Prof ; Franke, Andre, Prof ; Gearry, Richard B, Prof ; Goyette, Philippe, PhD ; Hakonarson, Hakon, Prof ; Halfvarson, Jonas, MD ; Hov, Johannes R, PhD ; Huang, Hailang, PhD ; Kennedy, Nicholas A, PhD ; Kupcinskas, Limas, Prof ; Lawrance, Ian C, Prof ; Lee, James C, PhD ; Satsangi, Jack, Prof ; Schreiber, Stephan, Prof ; Théâtre, Emilie, PhD ; van der Meulen-de Jong, Andrea E, MD ; Weersma, Rinse K, Prof ; Wilson, David C, Prof ; Parkes, Miles, PhD ; Vermeire, Severine, Prof ; Rioux, John D, Prof ; Mansfield, John, MD ; Silverberg, Mark S, PhD ; Radford-Smith, Graham, PhD ; McGovern, Dermot P B, Prof ; Barrett, Jeffrey C, Dr ; Lees, Charlie W, Dr
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frbrtype5
frbrgroupidcdi_FETCH-LOGICAL-1842t-98466ddd3524112808148a973b7243e496954bcaebca8cf77f24fa60241c898a3
rsrctypearticles
prefilterarticles
languageeng
creationdate2016
topic
0Adult
1Alleles
2Clinical Medicine
3Colitis
4Colitis, Ulcerative - genetics
5Colon
6Crohn Disease - genetics
7Crohns disease
8Family medical history
9Female
10Gastroenterologi
11Gastroenterology & hepatology
12Gastroenterology and Hepatology
13Gastroentérologie & hépatologie
14Genetic aspects
15Genetic Association Studies
16Genetic Predisposition to Disease
17Genetic research
18Genetics
19Genotype
20Genotype & phenotype
21Hepatocyte Growth Factor - genetics
22HLA-DRB1 Chains - genetics
23Human health sciences
24Humans
25Immunoassay
26Inflammatory bowel disease
27Internal Medicine
28Klinisk medicin
29Major Histocompatibility Complex - genetics
30Male
31Medical and Health Sciences
32Medical research
33Medicin och hälsovetenskap
34Medicine, Experimental
35Nod2 Signaling Adaptor Protein - genetics
36Phenotype
37Polymorphism, Single Nucleotide
38Proto-Oncogene Proteins - genetics
39Risk Assessment
40Sciences de la santé humaine
41Young Adult
toplevel
0peer_reviewed
1online_resources
creatorcontrib
0Cleynen, Isabelle, PhD
1Boucher, Gabrielle, MSc
2Jostins, Luke, PhD
3Schumm, L Philip, MA
4Zeissig, Sebastian, PhD
5Ahmad, Tariq, PhD
6Andersen, Vibeke, Prof
7Andrews, Jane M, Prof
8Annese, Vito, MD
9Brand, Stephan, Prof
10Brant, Steven R, MD
11Cho, Judy H, Prof
12Daly, Mark J, Prof
13Dubinsky, Marla, MD
14Duerr, Richard H, Prof
15Ferguson, Lynnette R, Prof
16Franke, Andre, Prof
17Gearry, Richard B, Prof
18Goyette, Philippe, PhD
19Hakonarson, Hakon, Prof
20Halfvarson, Jonas, MD
21Hov, Johannes R, PhD
22Huang, Hailang, PhD
23Kennedy, Nicholas A, PhD
24Kupcinskas, Limas, Prof
25Lawrance, Ian C, Prof
26Lee, James C, PhD
27Satsangi, Jack, Prof
28Schreiber, Stephan, Prof
29Théâtre, Emilie, PhD
30van der Meulen-de Jong, Andrea E, MD
31Weersma, Rinse K, Prof
32Wilson, David C, Prof
33Parkes, Miles, PhD
34Vermeire, Severine, Prof
35Rioux, John D, Prof
36Mansfield, John, MD
37Silverberg, Mark S, PhD
38Radford-Smith, Graham, PhD
39McGovern, Dermot P B, Prof
40Barrett, Jeffrey C, Dr
41Lees, Charlie W, Dr
42International Inflammatory Bowel Disease Genetics Consortium
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jtitleThe Lancet (British edition)
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delcategoryRemote Search Resource
fulltextfulltext
addata
au
0Cleynen, Isabelle, PhD
1Boucher, Gabrielle, MSc
2Jostins, Luke, PhD
3Schumm, L Philip, MA
4Zeissig, Sebastian, PhD
5Ahmad, Tariq, PhD
6Andersen, Vibeke, Prof
7Andrews, Jane M, Prof
8Annese, Vito, MD
9Brand, Stephan, Prof
10Brant, Steven R, MD
11Cho, Judy H, Prof
12Daly, Mark J, Prof
13Dubinsky, Marla, MD
14Duerr, Richard H, Prof
15Ferguson, Lynnette R, Prof
16Franke, Andre, Prof
17Gearry, Richard B, Prof
18Goyette, Philippe, PhD
19Hakonarson, Hakon, Prof
20Halfvarson, Jonas, MD
21Hov, Johannes R, PhD
22Huang, Hailang, PhD
23Kennedy, Nicholas A, PhD
24Kupcinskas, Limas, Prof
25Lawrance, Ian C, Prof
26Lee, James C, PhD
27Satsangi, Jack, Prof
28Schreiber, Stephan, Prof
29Théâtre, Emilie, PhD
30van der Meulen-de Jong, Andrea E, MD
31Weersma, Rinse K, Prof
32Wilson, David C, Prof
33Parkes, Miles, PhD
34Vermeire, Severine, Prof
35Rioux, John D, Prof
36Mansfield, John, MD
37Silverberg, Mark S, PhD
38Radford-Smith, Graham, PhD
39McGovern, Dermot P B, Prof
40Barrett, Jeffrey C, Dr
41Lees, Charlie W, Dr
aucorpInternational Inflammatory Bowel Disease Genetics Consortium
formatjournal
genrearticle
ristypeJOUR
atitleInherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study
jtitleThe Lancet (British edition)
addtitleLancet
date2016
risdate2016
volume387
issue10014
spage156
epage167
pages156-167
issn
00140-6736
11474-547X
eissn1474-547X
codenLANCAO
notes
0scopus-id:84954077730
1See appendix A for full list of investigators
2Contributed equally
abstractSummary 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).
copEngland
pubElsevier Ltd
pmid26490195
doi10.1016/S0140-6736(15)00465-1
oafree_for_read