Recent advances in IBD genetics have provided significant insights into the etiology of ulcerative colitis (UC) and Crohn's disease (UC), the two commonest forms of the inflammatory bowel diseases (IBD). Over 160 IBD susceptibility loci have been identified, but considerable progress is still required in order to: identify additional susceptibility loci;identify 'causal'variants at the known loci;to understand the functional effcts of the associated genetic variation;and to understand the interaction of these genes with the environment. The hypothesis underlying this proposal is based on the recognition that the IBDs are heterogeneous conditions. We believe that defining more homogenous groups (using several novel methods) will allow us to discover additional genetic variation associated with the IBDs. In order to facilitate further gene discovery and functional consequences of genetic variation, we will continue to recruit IBD-related subjects for both genetic and functional studies (aim 1). We will continue to perform and contribute large-scale genotyping datasets to IBDGC and IIBDGC projects (aim 1). The large size cohorts previously recruited, together with the recruitment and genotyping commitment from aim 1, will allow us to define adequately sized subgroups based upon clinical, demographic and histopathological criteria, which we believe will help define novel and unique genetic IBD associated variation (aim 2). We also propose to create homogenous subgroups through stratifying cases by known environmental factors (aims 2 and 3).
In aim 3, we will investigate the role of known IBD loci in influencing both the microbiome and metaproteame and therefore functional mucosal communities. We will also use these communities to define homogenous groups of individuals in order to identify unique variants associated with these communities. The proposed research and the identification of unique variation associated with sub-groups of these heterogeneous conditions will identify potential new therapeutic targets for the treatment and prevention of the IBDs, and also advance an individualized approach to managing these chronic, debilitating conditions.

Public Health Relevance

This project will study the genetic basis of the inflammatory bowel diseases, ulcerative colitis and Crohn's disease. Considerable progress has been made in identifying genes that predispose to these conditions. This study will build upon this progress using novel approaches to identify additional genes including novel disease subgroup stratification and novel statistical approaches for looking at gene-environmental interactions and the interaction of the host genome with the microbiome. These studies are highly relevant as the IBDs affect approximately 1.4 million Americans, and are a significant cause of morbidity and healthcare costs particularly in the very important second and third decades of life.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZDK1-GRB-G (O3))
Program Officer
Karp, Robert W
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Cedars-Sinai Medical Center
Los Angeles
United States
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Li, Dalin; Achkar, Jean-Paul; Haritunians, Talin et al. (2016) A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition. Gastroenterology 151:724-32
Kaur, Manreet; Panikkath, Deepa; Yan, Xiaofei et al. (2016) Perianal Crohn's Disease is Associated with Distal Colonic Disease, Stricturing Disease Behavior, IBD-Associated Serologies and Genetic Variation in the JAK-STAT Pathway. Inflamm Bowel Dis 22:862-9
Rivas, Manuel A; Graham, Daniel; Sulem, Patrick et al. (2016) A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. Nat Commun 7:12342
Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke et al. (2016) Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study. Lancet 387:156-67
Chu, Hiutung; Khosravi, Arya; Kusumawardhani, Indah P et al. (2016) Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 352:1116-20
Ye, Byong Duk; McGovern, Dermot P B (2016) Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility. Expert Rev Clin Immunol 12:1091-107
Guerrerio, Anthony L; Frischmeyer-Guerrerio, Pamela A; Huang, Chengrui et al. (2016) Increased Prevalence of Inflammatory Bowel Disease in Patients with Mutations in Genes Encoding the Receptor Subunits for TGFβ. Inflamm Bowel Dis 22:2058-62
Chuang, Ling-Shiang; Villaverde, Nicole; Hui, Ken Y et al. (2016) A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF. Gastroenterology 151:710-723.e2
Hoang-Yen Tran, D; Hoang-Ngoc Tran, D; Mattai, S A et al. (2016) Cathelicidin suppresses lipid accumulation and hepatic steatosis by inhibition of the CD36 receptor. Int J Obes (Lond) 40:1424-34
Kopylov, Uri; Boucher, Gabrielle; Waterman, Matti et al. (2016) Genetic Predictors of Benign Course of Ulcerative Colitis-A North American Inflammatory Bowel Disease Genetics Consortium Study. Inflamm Bowel Dis 22:2311-6

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