This project will focus on identifying genetic, regulatory activity, and gene expression changes that significantly contribute to IBD at molecular and clinical levels.
Terry Furey, PhD, Associate Professor of Genetics and Biology and Shehzad Sheikh, MD, PhD, Assistant Professor of Medicine and Genetics and Member of the Multidisciplinary Center for IBD Research and Treatment, have been awarded an R01 grant from NIDDK for their project titled “Integrative Genetic and Genomic Analyses in the Inflammatory Bowel Diseases”. The inflammatory bowel diseases (IBD), composed of Crohn’s disease (CD) and ulcerative colitis (UC), result from an inappropriately directed inflammatory response to the enteric microbiota in a genetically susceptible host. Genome wide association studies (GWAS) have linked 163 specific single nucleotide polymorphisms (SNPs) to IBD disease pathogenesis. Within these associated loci, there are over 5000 additional SNPs that are in linkage disequilibrium (LD) with the identified SNPs, and it is not known which of these contribute to IBD. Most of these SNPs map to non-coding regions of the genome, suggesting that many variants contribute to IBD by modifying gene regulatory element activity. The role of environmental factors such as the enteric microbiota in the initiation and perpetuation of inflammation in IBD is incontrovertible. Specifically, loss of lamina propria (LP) macrophage tolerance to the enteric microbiota is a central event in the initiation and progression of chronic intestinal inflammation. They hypothesize that DNA variation that impacts gene regulatory element activity significantly contributes to the differential host response to microbial stimuli between normal and IBD individuals. The primary goal of this proposal is to identify genetic, regulatory activity, and gene expression changes that significantly contribute to IBD at molecular and clinical levels. Genomic regions of nucleosome-depleted, open chromatin have been linked to all types of regulatory elements, and genome-wide assays to detect these are now available. The studies will determine open chromatin status, transcription levels, and genotypes for a panel of comprehensively phenotyped CD and UC patient tissue samples obtained from the non-inflamed section of the ascending colon. Similar data will be generated for non-IBD controls for comparison. Using these data, they will determine regulatory elements with genetically driven differential activity across a host of clinical and molecular IBD phenotypes. The long-term goals of this project are: 1) To fill the gap between our ability to detect genetic, chromatin, and gene expression variation linked to IBD and our ability to explain how that variation ultimately contributes to IBD; and 2) To provide a unique data resource for IBD investigators to access for their own studies.