PROJECT SUMMARY Inflammatory bowel disease (IBD) is a common and devastating immune-mediated disease in which the mucosal immune system abnormally recognizes the intestinal bacterial flora leading to chronic inflammation. Approximately, 1% of the US population is affected. The causes of Crohn's disease (CD) and ulcerative colitis (UC) lie in the interplay between host response genes and a microbiome with pathogenic properties. IBD incidence has leveled off in the developed world and rising in the newly industrialized world. In the US, we are witnessing a rising incidence in immigrants from low-risk parts of the world, particularly Hispanics. This provides an opportunity for discovery of disease pathogenesis towards a goal of prevention and improved therapies. Unfortunately, most genetic studies of IBD, including from the IBDGC, have focused on individuals of European ancestry from North America and Europe. Moreover, most clinical trials of IBD medications include too few Hispanics or Blacks and thus do not represent the totality of the affected population. Our group has a dedicated research interest on IBD in Latin-American immigrants and American-born Hispanic patients. We have published highly-cited studies of the genotype and phenotype of IBD in the Hispanic population of South Florida. We have also described disparities in medication usage and surgical rates. Important for the notion that IBD is caused by a gene-environment interaction, we have found that IBD is occurring faster in the last 20 years in immigrants from Latin-America. We have been very successful in our collection efforts because of our location and our commitment and engagement in the Hispanic community. We have a unique opportunity and obligation to study this disease within the Hispanic population. Miami-Dade County is over 50% Hispanic. The state of Florida has the 3rd largest Hispanic population and the most diverse in terms of countries of origin. We are poised with the support of an IBDGC grant to expand our collection efforts to the broader state of Florida. Genome-wide association studies (GWAS) have facilitated the discovery of previously unrecognized genes and pathways in IBD and provided the opportunity for unbiased exploration of the genomes of patients with IBD. We will explore genetic variation in a large set of US-born and foreign-born Hispanic IBD cases by focusing on targeted genomic, transcriptomic, and epigenetic differences between immigrant and first-generation Hispanic-Americans with IBD. We will edify how genes and environment interact to result in diverse phenotypic manifestations of IBD. Our group has particular expertise and interest in methods to fine-map previously identified risk loci and access the impact of local genetic ancestry on genotype-ancestry interactions in relation to phenotypic characteristics, with the goal of identifying genetic variation of functional significance. Our proposed studies will expand knowledge of disease phenotype an...