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.
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.
|Weiser, Matthew; Simon, Jeremy M; Kochar, Bharati et al. (2018) Molecular classification of Crohn's disease reveals two clinically relevant subtypes. Gut 67:36-42|
|Clerc, Florent; Novokmet, Mislav; Dotz, Viktoria et al. (2018) Plasma N-Glycan Signatures Are Associated With Features of Inflammatory Bowel Diseases. Gastroenterology 155:829-843|
|Šimurina, Mirna; de Haan, Noortje; Vu?kovi?, Frano et al. (2018) Glycosylation of Immunoglobulin G Associates With Clinical Features of Inflammatory Bowel Diseases. Gastroenterology 154:1320-1333.e10|
|Leonardi, Irina; Li, Xin; Semon, Alexa et al. (2018) CX3CR1+ mononuclear phagocytes control immunity to intestinal fungi. Science 359:232-236|
|Hinks, Anne; Marion, Miranda C; Cobb, Joanna et al. (2018) Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis. Arthritis Rheumatol 70:957-962|
|Hui, Ken Y; Fernandez-Hernandez, Heriberto; Hu, Jianzhong et al. (2018) Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. Sci Transl Med 10:|
|Schwerd, T; Bryant, R V; Pandey, S et al. (2018) NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease. Mucosal Immunol 11:562-574|
|Schirmer, Melanie; Franzosa, Eric A; Lloyd-Price, Jason et al. (2018) Dynamics of metatranscription in the inflammatory bowel disease gut microbiome. Nat Microbiol 3:337-346|
|Zhang, Hong; Zheng, Libo; Chen, Jeremy et al. (2017) The protection role of Atg16l1 in CD11c+dendritic cells in murine colitis. Immunobiology 222:831-841|
|Yoon, Soon Man; Haritunians, Talin; Chhina, Sultan et al. (2017) Colonic Phenotypes Are Associated with Poorer Response to Anti-TNF Therapies in Patients with IBD. Inflamm Bowel Dis 23:1382-1393|
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