Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype: Results from the IBDchip European project

Isabelle Cleynen, Juan R. González, Carolina Figueroa, Andre Franke, Dermot McGovern, Martin Bortlík, Bart J A Crusius, Maurizio Vecchi, Marta Artieda, Magdalena Szczypiorska, Johannes Bethge, David Arteta, Edgar Ayala, Silvio Danese, Ruud A. Van Hogezand, Julian Panés, Salvador Amado Peña, Milan Lukas, Derek P. Jewell, Stefan SchreiberSeverine Vermeire, Miquel Sans

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

Objective: Through genome-wide association scans and meta-analyses thereof, over 70 genetic loci (Crohn's disease (CD) single nucleotide polymorphisms (SNPs)) are significantly associated with CD. We aimed to investigate the influence of CD-SNPs and basic patient characteristics on CD clinical course, and develop statistical models to predict CD clinical course. Design: This retrospective study included 1528 patients with CD with more than 10 years of follow-up from eight European referral hospitals. CD outcomes of interest were ileal (L1), colonic (L2) and ileocolonic disease location (L3); stenosing (B2) or penetrating behaviour (B3); perianal disease; extraintestinal manifestations; and bowel resection. A complicated disease course was defined as stenosing or penetrating behaviour, perianal disease and/or bowel resection. Association between CD-SNPs or patient characteristics and specified outcomes was studied. Results: Several CD-SNPs and clinical characteristics were statistically associated with outcomes of interest. The NOD2 gene was the most important genetic factor, being an independent predictive factor for ileal location (p=2.02×10-06, OR=1.90), stenosing (p=3.16×10 -06, OR=1.82) and penetrating (p=1.26×10-02, OR=1.25) CD behaviours, and need for surgery (p=2.28×e-05, OR=1.73), and as such was also the strongest factor associated with a complicated disease course (p=6.86×10-06, OR=2.96). Immunomodulator (azathioprine/6-mercaptopurine and methotrexate) use within 3 years after diagnosis led to a reduction in bowel stenoses (p=1.48×10-06, OR=0.35) and surgical rate (p=1.71×10-07, OR=0.34). Association between each outcome and genetic scores, created using significant SNPs in the univariate analysis, revealed large differences in the probability of developing fistulising disease (IL23R, LOC441108, PRDM1, NOD2; p=9.64e-4, HR=1.43), need for surgery (IRGM, TNFSF15, C13ORF31, NOD2; p=7.12×10-03, HR=1.35), and stenosing disease (NOD2, JAK2, ATG16L1; p=3.01×10 -02, HR=1.29) among patients with low and high score. Conclusions: This large multicentre cohort study has found several genetic and clinical factors influencing the clinical course of CD. NOD2 and early immunomodulator use are the clinically most meaningful predictors for its clinical course.

Original languageEnglish
Pages (from-to)1556-1565
Number of pages10
JournalGut
Volume62
Issue number11
DOIs
Publication statusPublished - Nov 2013

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Crohn Disease
Phenotype
Single Nucleotide Polymorphism
Immunologic Factors
6-Mercaptopurine
Genetic Loci
Genome-Wide Association Study
Azathioprine
Statistical Models
Methotrexate
Multicenter Studies
Meta-Analysis
Pathologic Constriction
Cohort Studies
Referral and Consultation
Retrospective Studies

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype : Results from the IBDchip European project. / Cleynen, Isabelle; González, Juan R.; Figueroa, Carolina; Franke, Andre; McGovern, Dermot; Bortlík, Martin; Crusius, Bart J A; Vecchi, Maurizio; Artieda, Marta; Szczypiorska, Magdalena; Bethge, Johannes; Arteta, David; Ayala, Edgar; Danese, Silvio; Van Hogezand, Ruud A.; Panés, Julian; Peña, Salvador Amado; Lukas, Milan; Jewell, Derek P.; Schreiber, Stefan; Vermeire, Severine; Sans, Miquel.

In: Gut, Vol. 62, No. 11, 11.2013, p. 1556-1565.

Research output: Contribution to journalArticle

Cleynen, I, González, JR, Figueroa, C, Franke, A, McGovern, D, Bortlík, M, Crusius, BJA, Vecchi, M, Artieda, M, Szczypiorska, M, Bethge, J, Arteta, D, Ayala, E, Danese, S, Van Hogezand, RA, Panés, J, Peña, SA, Lukas, M, Jewell, DP, Schreiber, S, Vermeire, S & Sans, M 2013, 'Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype: Results from the IBDchip European project', Gut, vol. 62, no. 11, pp. 1556-1565. https://doi.org/10.1136/gutjnl-2011-300777
Cleynen, Isabelle ; González, Juan R. ; Figueroa, Carolina ; Franke, Andre ; McGovern, Dermot ; Bortlík, Martin ; Crusius, Bart J A ; Vecchi, Maurizio ; Artieda, Marta ; Szczypiorska, Magdalena ; Bethge, Johannes ; Arteta, David ; Ayala, Edgar ; Danese, Silvio ; Van Hogezand, Ruud A. ; Panés, Julian ; Peña, Salvador Amado ; Lukas, Milan ; Jewell, Derek P. ; Schreiber, Stefan ; Vermeire, Severine ; Sans, Miquel. / Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype : Results from the IBDchip European project. In: Gut. 2013 ; Vol. 62, No. 11. pp. 1556-1565.
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abstract = "Objective: Through genome-wide association scans and meta-analyses thereof, over 70 genetic loci (Crohn's disease (CD) single nucleotide polymorphisms (SNPs)) are significantly associated with CD. We aimed to investigate the influence of CD-SNPs and basic patient characteristics on CD clinical course, and develop statistical models to predict CD clinical course. Design: This retrospective study included 1528 patients with CD with more than 10 years of follow-up from eight European referral hospitals. CD outcomes of interest were ileal (L1), colonic (L2) and ileocolonic disease location (L3); stenosing (B2) or penetrating behaviour (B3); perianal disease; extraintestinal manifestations; and bowel resection. A complicated disease course was defined as stenosing or penetrating behaviour, perianal disease and/or bowel resection. Association between CD-SNPs or patient characteristics and specified outcomes was studied. Results: Several CD-SNPs and clinical characteristics were statistically associated with outcomes of interest. The NOD2 gene was the most important genetic factor, being an independent predictive factor for ileal location (p=2.02×10-06, OR=1.90), stenosing (p=3.16×10 -06, OR=1.82) and penetrating (p=1.26×10-02, OR=1.25) CD behaviours, and need for surgery (p=2.28×e-05, OR=1.73), and as such was also the strongest factor associated with a complicated disease course (p=6.86×10-06, OR=2.96). Immunomodulator (azathioprine/6-mercaptopurine and methotrexate) use within 3 years after diagnosis led to a reduction in bowel stenoses (p=1.48×10-06, OR=0.35) and surgical rate (p=1.71×10-07, OR=0.34). Association between each outcome and genetic scores, created using significant SNPs in the univariate analysis, revealed large differences in the probability of developing fistulising disease (IL23R, LOC441108, PRDM1, NOD2; p=9.64e-4, HR=1.43), need for surgery (IRGM, TNFSF15, C13ORF31, NOD2; p=7.12×10-03, HR=1.35), and stenosing disease (NOD2, JAK2, ATG16L1; p=3.01×10 -02, HR=1.29) among patients with low and high score. Conclusions: This large multicentre cohort study has found several genetic and clinical factors influencing the clinical course of CD. NOD2 and early immunomodulator use are the clinically most meaningful predictors for its clinical course.",
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T1 - Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype

T2 - Results from the IBDchip European project

AU - Cleynen, Isabelle

AU - González, Juan R.

AU - Figueroa, Carolina

AU - Franke, Andre

AU - McGovern, Dermot

AU - Bortlík, Martin

AU - Crusius, Bart J A

AU - Vecchi, Maurizio

AU - Artieda, Marta

AU - Szczypiorska, Magdalena

AU - Bethge, Johannes

AU - Arteta, David

AU - Ayala, Edgar

AU - Danese, Silvio

AU - Van Hogezand, Ruud A.

AU - Panés, Julian

AU - Peña, Salvador Amado

AU - Lukas, Milan

AU - Jewell, Derek P.

AU - Schreiber, Stefan

AU - Vermeire, Severine

AU - Sans, Miquel

PY - 2013/11

Y1 - 2013/11

N2 - Objective: Through genome-wide association scans and meta-analyses thereof, over 70 genetic loci (Crohn's disease (CD) single nucleotide polymorphisms (SNPs)) are significantly associated with CD. We aimed to investigate the influence of CD-SNPs and basic patient characteristics on CD clinical course, and develop statistical models to predict CD clinical course. Design: This retrospective study included 1528 patients with CD with more than 10 years of follow-up from eight European referral hospitals. CD outcomes of interest were ileal (L1), colonic (L2) and ileocolonic disease location (L3); stenosing (B2) or penetrating behaviour (B3); perianal disease; extraintestinal manifestations; and bowel resection. A complicated disease course was defined as stenosing or penetrating behaviour, perianal disease and/or bowel resection. Association between CD-SNPs or patient characteristics and specified outcomes was studied. Results: Several CD-SNPs and clinical characteristics were statistically associated with outcomes of interest. The NOD2 gene was the most important genetic factor, being an independent predictive factor for ileal location (p=2.02×10-06, OR=1.90), stenosing (p=3.16×10 -06, OR=1.82) and penetrating (p=1.26×10-02, OR=1.25) CD behaviours, and need for surgery (p=2.28×e-05, OR=1.73), and as such was also the strongest factor associated with a complicated disease course (p=6.86×10-06, OR=2.96). Immunomodulator (azathioprine/6-mercaptopurine and methotrexate) use within 3 years after diagnosis led to a reduction in bowel stenoses (p=1.48×10-06, OR=0.35) and surgical rate (p=1.71×10-07, OR=0.34). Association between each outcome and genetic scores, created using significant SNPs in the univariate analysis, revealed large differences in the probability of developing fistulising disease (IL23R, LOC441108, PRDM1, NOD2; p=9.64e-4, HR=1.43), need for surgery (IRGM, TNFSF15, C13ORF31, NOD2; p=7.12×10-03, HR=1.35), and stenosing disease (NOD2, JAK2, ATG16L1; p=3.01×10 -02, HR=1.29) among patients with low and high score. Conclusions: This large multicentre cohort study has found several genetic and clinical factors influencing the clinical course of CD. NOD2 and early immunomodulator use are the clinically most meaningful predictors for its clinical course.

AB - Objective: Through genome-wide association scans and meta-analyses thereof, over 70 genetic loci (Crohn's disease (CD) single nucleotide polymorphisms (SNPs)) are significantly associated with CD. We aimed to investigate the influence of CD-SNPs and basic patient characteristics on CD clinical course, and develop statistical models to predict CD clinical course. Design: This retrospective study included 1528 patients with CD with more than 10 years of follow-up from eight European referral hospitals. CD outcomes of interest were ileal (L1), colonic (L2) and ileocolonic disease location (L3); stenosing (B2) or penetrating behaviour (B3); perianal disease; extraintestinal manifestations; and bowel resection. A complicated disease course was defined as stenosing or penetrating behaviour, perianal disease and/or bowel resection. Association between CD-SNPs or patient characteristics and specified outcomes was studied. Results: Several CD-SNPs and clinical characteristics were statistically associated with outcomes of interest. The NOD2 gene was the most important genetic factor, being an independent predictive factor for ileal location (p=2.02×10-06, OR=1.90), stenosing (p=3.16×10 -06, OR=1.82) and penetrating (p=1.26×10-02, OR=1.25) CD behaviours, and need for surgery (p=2.28×e-05, OR=1.73), and as such was also the strongest factor associated with a complicated disease course (p=6.86×10-06, OR=2.96). Immunomodulator (azathioprine/6-mercaptopurine and methotrexate) use within 3 years after diagnosis led to a reduction in bowel stenoses (p=1.48×10-06, OR=0.35) and surgical rate (p=1.71×10-07, OR=0.34). Association between each outcome and genetic scores, created using significant SNPs in the univariate analysis, revealed large differences in the probability of developing fistulising disease (IL23R, LOC441108, PRDM1, NOD2; p=9.64e-4, HR=1.43), need for surgery (IRGM, TNFSF15, C13ORF31, NOD2; p=7.12×10-03, HR=1.35), and stenosing disease (NOD2, JAK2, ATG16L1; p=3.01×10 -02, HR=1.29) among patients with low and high score. Conclusions: This large multicentre cohort study has found several genetic and clinical factors influencing the clinical course of CD. NOD2 and early immunomodulator use are the clinically most meaningful predictors for its clinical course.

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