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. (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.