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P361. Whole-transcript human gene expression pathway analysis in Crohn's disease

O. Palmieri1, A. Latiano1, R. Maglietta2, B. Fabrizio1, D. Scimeca1, G. Biscaglia1, O. Palumbo3, M. Carella3, N. Ancona2, A. Andriulli1, V. Annese4

1Unit of Gastroenterology, IRCCS-CSS Hospital, San Giovanni Rotondo, Italy; 2ISSIA–C.N.R., Bari, Italy; 3Medical Genetics, IRCCS-CSS Hospital, San Giovanni Rotondo, Italy; 4Unit of Gastroenterology SOD2, AOU Careggi, Florence, Italy

More than 70 susceptibility genes have been detected by genome wide screening-approaches in Crohn's disease (CD). However, studies which evaluates mucosal expression of candidate genes are scarce. This study was designed to investigate the level of whole-transcript gene expression in the colonic mucosa of patients with CD during an active phase of disease, using pathway analysis.

Methods: Fifteen consecutive CD patients (11 male), colonic mucosal biopsies were taken at either inflamed and adjacent non-inflamed area of the gut. RNA preparation, of the Affymetrix Genechip Human Gene 1.0 ST Array was done according to the manufacturer's instructions. Each expression profile was composed of 20215 genes. Differential expression was assessed by using paired t-test statistics, the False Discovery Rate (FDR) was evaluated with the Storey's method, and pathway enriched analysis was assessed by using Random Set.

Results: We identify 434 genes with an altered expression in inflamed areas compared with non inflamed areas with p value <0.001, and False Discovery Rate (FDR) <0.05. The top 10 deregulated genes were: CRAT, THRA, C10ORF58, SEC61B, PRKD1, AVPR1A, PDLIM, SPATA6, SEC24B, and PRKCZ (p < 0.00003, FDR < 0.03). Subsequently, to further elucidate the global changes during inflammation, we assessed deregulation of 639 pathways annotated in Canonical Pathways (C2) and 825 gene sets annotated in Biological Processes of Gene Ontology (C5), thus identifying 34 pathways (p < 0.01). Of these, 6 pathways were enriched in the non inflamed tissues and 28 in the inflamed tissues. When we grouped the pathways in classes, we identified 5 super-pathways (p < 0.005, FDR < 0.005). Of these, 4 have been merged to represent the regulation of biological processes involved in inflammation and cellular homeostasis: cellular component movement, regulation of biological process, response to stimulus and signaling molecules, and interaction. They were enriched in inflamed tissues. The fifth pathway, involved in the lipid metabolism, was enriched in non inflamed tissues. The hit deregulated 5 genes of the super-pathways were: ECHS1, ACOX1, CPT1A, CPT2, and PECI (p < 0.0002, FDR < 0.04) for lipid metabolism; L8RB, SELE, SELL, SELP and TGFB2 (p < 0.003, FDR < 0.05) for cellular component movement; ERBB2, PTHLH, TGFBR1, TNFSF13B, and IL1B (p < 0.001, FDR < 0.05) for regulation of biological process; CBLC, PIK3R1, SOS2, PTAFR, and ADM (p < 0.0006, FDR < 0.04) for response to stimulus; and CSF2RA, IL8RA, IL8RB, OSMR, IL1RAP (p < 0.001, FDR < 0.05) for signaling molecules and interaction.

Conclusions: 434 deregulated genes in colonic mucosa of CD patients were identified. The identified up regulated expression of genes involved in fundamental biological processes suggests their important role in a state of chronic inflammation such as CD. Of interest, the identified lipid metabolism pathway underlies that decreased availability of fatty acid levels linked to the inflammatory status of the affected tissue might become particularly relevant in metabolically “challenged” intestinal epithelial cells.