Identification of novel genes involved in the pathogenesis of inflammatory bowel disease using high-throughput microarray expression screening
The etiology of the two main forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC) remains unknown; however, a combination of environmental and genetic factors participate in the etiopathogenesis of IBD, including microbial, dietary, immune, inflammatory, and intestinal permeability factors. The advent of microarray expression screening facilitates the investigation of complex, polygenic diseases by enabling the scientist to monitor the gene transcript levels of the whole genome. As a first step, a comparison was made between two such methods, namely cDNA-based and oligonucleotide-based microarray platforms. For a given set of genes known to be present on both platforms, there was moderate overlap in 'present' or 'absent' gene calls and weak correlation in the expression levels of transcripts detected. Keeping these results in mind, both cDNA- and oligo-based microarrays were used to perform whole-genome expression profiling in colonic mucosa biopsies obtained from IBD patients and normal controls (> 80 individuals), and the resulting microarray datasets were analysed separately. This study identified many functional groups of gene transcripts that were differentially expressed between inflamed/non-inflamed IBD and normal controls. Though many different lines of investigation could have been pursued, specific focus was placed on immune and inflammatory response, oncogenesis, and structure and permeability. Particular attention was further limited to the role of genes involved in Wnt pathway and cell-cell adhesion in IBD. Selected genes of interest were further verified using an independent technique (quantitative real-time PCR) in a larger cohort of IBD patients, disease-specificity controls and normal controls (>300 individuals). Taken together, a comprehensive whole-genome expression analysis revealed novel genes (CYLD, DMBT1, CEACAM1, CSNKD1, PDLIM5, ROCK1, CDH11, SPINK5, PRKCB1, TJP2, VCL, ADAM12, FOXL1, TCF7, TCF7L2, TCF4, EMP3, JUNB) that are associated with the pathogenesis of IBD and serve to provide fresh insight into the mechanisms of this complex disease.
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