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Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype: results from the IBDchip European Project
  1. Isabelle Cleynen1,
  2. Juan R González2,
  3. Carolina Figueroa2,
  4. Andre Franke3,
  5. Dermot McGovern4,
  6. Martin Bortlík5,
  7. Bart J A Crusius6,
  8. Maurizio Vecchi7,
  9. Marta Artieda8,
  10. Magdalena Szczypiorska8,
  11. Johannes Bethge3,
  12. David Arteta8,
  13. Edgar Ayala2,
  14. Silvio Danese9,
  15. Ruud A van Hogezand10,
  16. Julian Panés2,
  17. Salvador Amado Peña6,
  18. Milan Lukas5,
  19. Derek P Jewell4,
  20. Stefan Schreiber3,
  21. Severine Vermeire1,
  22. Miquel Sans2,11
  1. 1Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
  2. 2Department of Gastroenterology, Hospital Clínic i Provincial/IDIBAPS, Barcelona, Spain
  3. 3 Institute for Clinical Molecular Biology, Christian Albrechts University Kiel, Kiel, Germany
  4. 4 Nuffield Department of Medicine, University of Oxford, Oxford, UK
  5. 5 Gastroenterology Center, 4th Internal Department, General Faculty Hospital, Charles University, Prague, Czech Republic
  6. 6 Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands
  7. 7 Department of Gastroenterology, IRCCS Policlinico San Donato, University of Milan, Milan, Italy
  8. 8 Progenika Biopharma, Derio, Spain
  9. 9 IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Italy
  10. 10 Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
  11. 11 Department of Digestive Diseases, Centro Médico Teknon, Barcelona, Spain
  1. Correspondence to Dr Miquel Sans, Department of Digestive Diseases, Centro Médico Teknon, Barcelona, Spain; sans{at}dr.teknon.es

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.

  • Crohn's Disease
  • Inflammatory Bowel Disease
  • IBD – Genetics
  • Genetic Polymorphisms
  • IBD

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