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Characterization of intestinal gene expression profiles in Crohn's disease by genome-wide microarray analysis

Noble, Colin L. MD1,2,*; Abbas, Alexander R. PhD3; Lees, Charles W. PhD1; Cornelius, Jennine PhD2; Toy, Karen BS4; Modrusan, Zora PhD4; Clark, Hilary F. PhD3; Arnott, Ian D. MD1; Penman, Ian D. MD1; Satsangi, Jack M Phil1,†; Diehl, Lauri PhD2,†

doi: 10.1002/ibd.21263
Original Basic Science Articles: Genome-wide Microarray Analysis of CD: Original Article

Background: Genome-wide microarray expression analysis creates a comprehensive picture of gene expression at the cellular level. The aim of this study was to investigate differential intestinal gene expression in patients with Crohn's disease (CD) and controls with subanalysis of confirmed CD susceptibility genes, associated pathways, and cell lineage.

Methods: In all, 172 biopsies from 53 CD and 31 control subjects were studied. Paired endoscopic biopsies were taken at ileocolonoscopy from five specific anatomical locations including the terminal ileum (TI) for RNA extraction and histology. The 41,058 expression sequence tags were analyzed using the Agilent platform.

Results: Analysis of all CD biopsies versus controls showed 259 sequences were upregulated and 87 sequences were downregulated. Upregulated genes in CD included SAA1 (fold change [FC] +7.5, P = 1.47 × 10−41) and REGL (FC +7.3, P = 2.3 × 10−16), whereas cellular detoxification genes including-SLC14A2 (FC-2.49, P = 0.00002) were downregulated. In the CD TI biopsies diubiquitin (FC+11.3, P < 1 × 10−45), MMP3 (FC+7.4, P = 1.3 × 10−11), and IRTA1 (FC-11.4, P = 4.7 × 10−12) were differentially expressed compared to controls. In the colon SAA1 (FC+6.3, P = 5.3 × 10−8) was upregulated and thymic stromal lymphopoietin (TSLP) (FC-2.3, P = 2.7 × 10−6) was downregulated comparing noninflamed CD and control biopsies, and the colonic inflammatory CD signature was characterized by downregulation of the organic solute carriers-SLC38A4, SLC26A2, and OST alpha. Of CD susceptibility genes identified by genome-wide association scan IL-23A, JAK2, and STAT3 were upregulated in the CD group, confirming the dysregulation of Th17 signaling.

Conclusions: These data characterize the dysregulation of a series of specific inflammatory pathways highlighting potential pathogenic mechanisms as well as areas for translation to therapeutic targets. (Inflamm Bowel Dis 2010)

1Gastrointestinal Unit, University of Edinburgh, Western General Hospital, Edinburgh, UK

2Department of Pathology, Genentech Inc., South San Francisco, California

3Department of Bioinformatics, Genentech Inc., South San Francisco, California

4Microarray Department, Genentech Inc., South San Francisco, California

*Reprints: Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, EH4 2XU, UK

Email: noblecolin@hotmail.com

Received for publication 15 January 2010; Accepted 25 January 2010.

Published online 19 April 2010 in Wiley Online Library (wileyonlinelibrary.com).

The last two are joint senior authors.

Additional supporting information may be found in the online version of this article.

© Crohn's & Colitis Foundation of America, Inc.
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