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

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.
October 2008
Gut;Oct2008, Vol. 57 Issue 10, p1398
Academic Journal
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.


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