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Gut. 2008 Oct;57(10):1398-405. doi: 10.1136/gut.2008.148395. Epub 2008 Jun 3.

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

Author information

  • 1Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, EH4 2XU, UK. noblecolin@hotmail.com

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. (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.

[PubMed - indexed for MEDLINE]
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