title: Molecular classification of Crohn's disease reveals two clinically relevant subtypes.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Weiser
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Jeremy M
authors.identifier: 0000-0003-3906-1663
authors.initials: JM
authors.lastname: Simon
authors.affiliation: Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Bharati
authors.initials: B
authors.lastname: Kochar
authors.affiliation: Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Adelaide
authors.initials: A
authors.lastname: Tovar
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Israel
authors.affiliation: Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Robinson
authors.affiliation: Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Gipson
authors.affiliation: Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Schaner
authors.affiliation: Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Herfarth
authors.affiliation: Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: R Balfour
authors.initials: RB
authors.lastname: Sartor
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Dermot P B
authors.initials: DPB
authors.lastname: McGovern
authors.affiliation: Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Reza
authors.initials: R
authors.lastname: Rahbar
authors.affiliation: Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Sadiq
authors.affiliation: Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Koruda
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Terrence S
authors.initials: TS
authors.lastname: Furey
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Shehzad Z
authors.initials: SZ
authors.lastname: Sheikh
mesh_terms: D000328:Adult; D000367:Age Factors; D016022:Case-Control Studies; D002648:Child; D003106:Colon / Q000378:metabolism; D003424:Crohn Disease / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D007082:Ileum / Q000378:metabolism; D008297:Male; D010641:Phenotype; D025341:Principal Component Analysis; D011379:Prognosis
keywords: CROHN'S DISEASE; ENERGY METABOLISM; GENE REGULATION; IBD CLINICAL; RNA EXPRESSION