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

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. (chi(2)= 25.1, p < 0.0001). Developmental genes, homeobox protein A13 ( HOXA13), (p= 2.3x10(-16)), HOXB13 (p < 1x10(-45)), glioma-associated oncogene 1 ( GLI1) ( p= 4.0x10(-24)), and GLI3 (p= 2.1x10(-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= 6.95x10(-7), respectively), matrix metalloproteinase 3 (MMP3) (p= 5.6x10(-10)) and MMP7 (p= 2.3x10(-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.