TITLE

Regional variation in gene expression in the healthy colon is dysregulated in ulcerative colitis

AUTHOR(S)
Noble, C. L.; Abbas, A. A.; Cornelius, J.; Lees, C. W.; Ho, G.-T.; Toy, K.; Modrusan, Z.; Pal, N.; Zhong, F.; Chalasani, S.; Clark, H.; Arnott, I. D.; Penman, I. D.; Satsangi, J.; Diehl, L.
PUB. DATE
October 2008
SOURCE
Gut;Oct2008, Vol. 57 Issue 10, p1398
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Objective: To investigate differential intestinal gene expression in patients with ulcerative colitis and in controls. Design: Genome-wide expression study (41 058 expression sequence tags, 215 biopsies). Setting: Western General Hospital, Edinburgh, UK, and Genentech, San Francisco, USA. Patients: 67 patients with ulcerative colitis and 31 control subjects (23 normal subjects and 8 patients with inflamed non-inflammatory bowel disease biopsies). Interventions: Paired endoscopic biopsies were taken from 5 specific anatomical locations for ANA extraction and histology. The Agilent microarray platform was used and confirmation of results was undertaken by real time polymerase chain reaction and immunohistochemistry. Results: In healthy control biopsies, cluster analysis showed differences in gene expression between the right and left colon. (χ2 = 25.1, p<0.0001). Developmental genes, homeobox protein A13 (HOXA13), (p = 2.3×10-16), HOXB13 (p<1 × 10-45), glioma-associated oncogene 1 (GLI1) (p = 4.0 × 10-24), and GLI3 (p = 2.1 × 10-28) primarily drove this separation. When all ulcerative colitis biopsies and control biopsies were compared, 143 sequences had a fold change of >1.5 in the ulcerative colitis biopsies (0.01 >p>10-45) and 54 sequences had a fold change of <-1.5 (0.01 >p>10-20). Differentially upregulated genes in ulcerative colitis included serum amyloid A1 (SAA1) (p<10-45) the alpha defensins 5 and 6 (DEFA5 and 6) (p = 0.00003 and p = 6.95 × 10-7, respectively), matrix metalloproteinase 3 (MMP3) (p = 5.6 × 10-10) and MMP7 (p = 2.3 × 10-7). Increased DEFA5 and 6 expression was further characterised to Paneth cell metaplasia by immunohistochemistry and in situ hybridisation. Sub-analysis of the inflammatory bowel disease 2 (IBD2) and IBD5 loci, and the ATP-binding cassette (ABC) transporter genes revealed a number of differentially regulated genes in the ulcerative colitis biopsies. Conclusions: Key findings are the expression gradient in the healthy adult colon and the involvement of novel gene families, as well as established candidate genes in the pathogenesis of ulcerative colitis.
ACCESSION #
34640822

 

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