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Molecular classification of Crohn's disease reveals two clinically relevant subtypes
  1. Matthew Weiser1,2,
  2. Jeremy M Simon1,
  3. Bharati Kochar2,3,
  4. Adelaide Tovar3,4,
  5. Jennifer W Israel1,
  6. Adam Robinson3,
  7. Gregory R Gipson3,
  8. Matthew S Schaner3,
  9. Hans H Herfarth3,
  10. R Balfour Sartor3,
  11. Dermot P B McGovern5,
  12. Reza Rahbar6,
  13. Timothy S Sadiq6,
  14. Mark J Koruda6,
  15. Terrence S Furey1,2,7,
  16. Shehzad Z Sheikh1,2,3,4
  1. 1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  2. 2Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  3. 3Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  4. 4Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  5. 5F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
  6. 6Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  7. 7Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  1. Correspondence to Dr Shehzad Z Sheikh, Departments of Medicine and Genetics, University of North Carolina at Chapel Hill, 7340B Medical Biomolecular Research Building, Chapel Hill, NC 27517, USA; sheisx{at}med.unc.edu

Abstract

Objective The clinical presentation and course of Crohn's disease (CD) is highly variable. We sought to better understand the cellular and molecular mechanisms that guide this heterogeneity, and characterise the cellular processes associated with disease phenotypes.

Design We examined both gene expression and gene regulation (chromatin accessibility) in non-inflamed colon tissue from a cohort of adult patients with CD and control patients. To support the generality of our findings, we analysed previously published expression data from a large cohort of treatment-naïve paediatric CD and control ileum.

Results We found that adult patients with CD clearly segregated into two classes based on colon tissue gene expression—one that largely resembled the normal colon and one where certain genes showed expression patterns normally specific to the ileum. These classes were supported by changes in gene regulatory profiles observed at the level of chromatin accessibility, reflective of a fundamental shift in underlying molecular phenotypes. Furthermore, gene expression from the ilea of a treatment-naïve cohort of paediatric patients with CD could be similarly subdivided into colon-like and ileum-like classes. Finally, expression patterns within these CD subclasses highlight large-scale differences in the immune response and aspects of cellular metabolism, and were associated with multiple clinical phenotypes describing disease behaviour, including rectal disease and need for colectomy.

Conclusions Our results strongly suggest that these molecular signatures define two clinically relevant forms of CD irrespective of tissue sampling location, patient age or treatment status.

  • CROHN'S DISEASE
  • GENE REGULATION
  • RNA EXPRESSION
  • ENERGY METABOLISM
  • IBD CLINICAL

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Footnotes

  • MW, JMS, TSF and SZS contributed equally.

  • Contributors MW, JMS, BK, AT, AR, GRG, MSS and DPBM acquired data. MW, JMS and JWI analysed and interpreted data. MW and JMS prepared figures, drafted and revised the manuscript. RBS, HHH, RR, TSS and MJK provided help with tissue acquisition and patient phenotyping. SZS and TSF designed and supervised the study, acquired, analysed and interpreted the data, drafted and revised the manuscript and obtained funding. SZS conceptualised the study and acted as study sponsor. All authors uphold the integrity of the work, approved the manuscript in its entirety and are accountable for all aspects of the work.

  • Funding National Institute of Environmental Health Sciences (R01-ES024983), National Institute of Diabetes and Digestive and Kidney Diseases (P01-DK046763, P30-DK034987, R01-DK094779, T32-DK007634 and U01-DK062413), American Gastroenterological Association Research Scholar Award (SZS), Broad Medical Research Program, Crohn’s and Colitis Foundation of Americaߣs Career Development Award (SZS) and Microbiome Consortium, UNC Team Translational Science Award, and Helmsley Trust SHARE 2, Project 3.

  • Competing interests None declared.

  • Ethics approval University of North Carolina IRB.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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