Objective: The aim of this study was to investigate differential intestinal gene expression in patients with ulcerative colitis (UC) and controls.
Design: Genome wide expression study (41058 expression sequence tags, 215 biopsies).
Setting: Western General Hospital, Edinburgh, UK, Genentech Inc, San Francisco, USA. Patients: 67 UC and 31 control subjects- 23 normal and 8 inflamed non-inflammatory bowel disease patients.
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 PCR 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 HOXA13, (p=2.3x10-16), HOXB13 (p <1x10-45), GLI1 (p=4.0x10-24), and GLI3 (p=2.1x10-28) primarily drove this separation. When all UC biopsies and control biopsies were compared, 143 sequences had a fold change of >1.5 in the UC 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 UC included SAA1 (p<10-45) the alpha defensins, DEFA5&6 (p=0.00003 and p=6.95x10-7 respectively), MMP3 (p=5.6x10-10) and MMP7 (p=2.3x10-7). Increased DEFA5&6 expression was further characterized to Paneth cell metaplasia by immunohistochemistry and in-situ hybridization. Sub-analysis of the IBD2 & IBD5 loci, and the ABC transporter genes revealed a number of differentially regulated genes in the UC 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 UC.
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