Genomic and Immunologic Characterization of Inflammatory Bowel Disease and its Phenotypes

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Project Summary/Abstract To date more than 200 genetic variants are known to be associated with inflammatory bowel disease (IBD). The majority of these have been identified by genome-wide association studies (GWAS). The individual Genetic Research Centers (GRCs) and the collective NIDDK IBD Genetics Consortium have successfully interacted for the last fifteen years to lead many of these discoveries. However, despite significant progress it is still unknown how the majority of these variants or other risk factors lead to development of IBD and its two major subtypes - Crohn’s disease (CD) and ulcerative colitis (UC). Answering these questions is critical to advancing our knowledge of IBD pathophysiology. Since 2002, Dr. Silverberg has established a very large, comprehensive registry of well characterized, longitudinally followed IBD patients at Mount Sinai Hospital in addition to accompanying biospecimens stored at his laboratory at the Lunenfeld-Tanenbaum Research Institute to facilitate research in IBD. Utilizing these resources and applying new expertise in cellular, genomic and immune profiling, it is anticipated that the proposed studies will help to make significant progress in the unmet needs described above. The IBDGC working together with the UTGRC will study comprehensively the genetic architecture of non-European ancestry IBD populations and utilize the power of its infrastructure to better elucidate the pathophysiology of acute severe ulcerative colitis and perianal Crohn’s disease. The UTGRC, specifically, will advance the understanding of UC pathophysiology by integrating imaging mass cytometry, spatial transcriptomics and scRNA-seq, in conjunction with tissue-associated microbiome analysis, to develop a comprehensive understanding of the immune, genomic, cellular and microbial factors that contribute to persistent histologic inflammation and mechanisms of clinical relapse in UC. Utilizing the power of these technologies, also provides a unique opportunity to go “back in time” to study critical events that lead to the development of colorectal cancer in UC – a poorly understood complication with significant mortality. By applying similar techniques in a retrospective cohort, the cellular and immune factors that lead to treatment refractory CD. Despite the progress in advanced biologic therapy, there are still a significant portion of patients who fail multiple therapies and have persistent inflammation. Taken together, through the studies proposed, it is anticipated that significant advances will be made toward better understanding the functional biology of IBD genetic variation and to enable the translation of these data to clinically meaningful tools that will lead improved outcomes for individuals affected by IBD.