Regional variation in gene expression in the healthy colon is dysregulated in ulcerative colitis. Issue 10 (3rd June 2008)

• Record Type: Journal Article
• Authors: Noble, C L; Abbas, A R; 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
• Is Part Of: Gut. Volume 57:Issue 10(2008)
• Page Start: 1398
• Page End: 1405
• Publication Date: 2008-06-03
• Subjects: Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2008.148395
• Languages: English
• ISSNs: 0017-5749

Abstract

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 RNA 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. (χ 2 = 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.