New Bioinformatics Approach to Analyze Gene Expressions and Signaling Pathways Reveals Unique Purine Gene Dysregulation Profiles that Distinguish Between CD and UC

Background: Expression of purine genes is modulated by inflammation or experimental colitis and altered expression leads to disrupted gut function. We Studied purine gene dysregulation profiles in inflammatory bowel disease (IBD) and determined whether they call distinguish between Crohn's disease (CD) and ulcerative colitis (UC) using Pathway Analysis and a new Comparative Analysis of Gene Expression and Selection (CAGES) method. Methods: Raw datasets for 22 purine genes and 36 probe-sets from National Center for Biotechnology Information (NCBI) GEO (Gene Expression Omnibus) (http://www.ncbi.nlm.nih.gov/projects/geo/) geo/) were analyzed by National Cancer Institute (NCI) Biological Resources Branch (BRB) array tools for random-variance Of multiple/36 i-tests in colonic mucosal biopsies or peripheral blood mononuclear cells (PBMCs) of CD, UC or control subjects. Dysregulation Occurs in 59% of purine genes in IBD including ADORA3, CD7.3, ADORA2A, ADORA2B, ADAR. AMPD2. AMPD3. DPP4, P2RY5, P2RY6, P2RY13, P2RY14. and P2RX5. Results: In CD biopsies. expression of ADORA3, AMPD3. P2RY13, and P2RY-5 were negatively correlated with acute inflammatory score, Crohn's Disease Activity Index (CDAI) or disease chronicity; P2RY14 was positively correlated in UC. In mucosal biopsies or PBMCs, CD and UC were distinguished by unique patterns of dysregulation (up- or downregulation) ill purine genes. Purine gene dysregulation differs between PBMCs and biopsies and possibly between sexes for each disease. Ingenuity Pathway Anal-ysis (IPA) revealed significant associations between alterations ill the expression of CD73 (upregulation) or ADORA3 (downregulation and inflammatory or purine genes (<= 10% of 57 genes) as well as G-protein coupled receptors. cAMP-dependent, and inflainnialory pathways: IPA distinguishes CD from UC. Conclusion: CAGES and Pathway Analysis provided novel evidonce thin UC and CD have distinct purine gene dysregulation signatures in association with inflammation. cAMP. or other singnaling pathways. Disease-specific purine gene signature profiles and pathway associations may he of therapeutic, diagnostic, and functional relevance. (Inflamm Bowel Dis 2009:15.-971-984)