The inflammatory bowel diseases (IBD) are comprised of Crohn's disease and ulcerative colitis and affect approximately 1.4 million Americans. Present medical therapies are incompletely effective. Enormous progress in defining genes contributing to IBD has been made possible through large Consortial efforts which leverage large sample sizes and complementary expertise. We present new data from the Immunochip, a collaborative international effort involving the analysis of over 75,000 samples that has resulted in the identification of 163 loci associated with IBD. A major goal of the field, moving forward, is to derive a more cohesive picture of IBD pathogenesis which moves from identifying myriad genetic loci to an approach which draws out whole pathways to deepen our understanding of the biology of the disease.
In Specific Aim 1, we propose to actively participate as a genetics research center (GRC) within the larger NIDDK IBD Genetics Consortium. Future progress will be enhanced by drawing in investigators with complementary expertise. In addition to present genetic, clinical and statistical expertise in the Yale GRC, we have added expertise in mucosal immunology and host-mycobacterial interactions. We will continue to provide sample material attached to relevant information useful for genetic and genomic studies.
In Specific Aim 2, we propose to define the underlying genetic architecture of IBD that has been shaped by host-microbe interactions. We identify evidence for natural selection driving many of association signals, likely driven by host-microbial interactions. We have identified a new IBD association to a region on chromosome 19q13 containing the LILR-KIR gene families. This region has been profoundly shaped by balancing selection, and a complete genetic definition of this region has been hampered by phasing challenges. We propose an innovative approach to define genetic variation in this region through long-range sequence reads in diverse populations that will resolve present phasing challenges. A striking overlap of IBD loci with mycobacterial susceptibility loci is observed, and a NOD2- focused analysis of a macrophage-enriched inflammatory module identifies additional IBD-associated genes nearby in the network that modulate host responses to mycobacterial infection. In order to provide a more cohesive understanding of the functional genomic responses, we propose studies to compare the expression and functional responses of human macrophages in response to mycobacterial infection between IBD patients and controls, and across populations. Combined with integrated, tissue-based Bayesian network analyses, these studies will deepen our understanding of the underlying mechanisms of IBD. This understanding is critical for the development of novel therapies to improve our treatment of patients affected by these often debilitating disorders.
A large number of genetic regions have now been associated with inflammatory bowel disease. Understanding how these genes connect into altered biologic pathways and networks will require integrating genetic data with expression-based datasets. This understanding will be critical to the development of improved therapies for these disorders.
|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:|
|Misra, Ravi; Arebi, Naila (2017) Re: Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease. Gastroenterology 152:2082-2083|
|Yan, Jie; Hedl, Matija; Abraham, Clara (2017) An inflammatory bowel disease-risk variant in INAVA decreases pattern recognition receptor-induced outcomes. J Clin Invest 127:2192-2205|
|Lahiri, Amit; Hedl, Matija; Yan, Jie et al. (2017) Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes. Nat Commun 8:15614|
|Huang, Hailiang; Fang, Ming; Jostins, Luke et al. (2017) Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature 547:173-178|
|Hinks, A; Bowes, J; Cobb, J et al. (2017) Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases. Ann Rheum Dis 76:765-772|
|Yadav, Pankaj; Ellinghaus, David; Rémy, Gaëlle et al. (2017) Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice. Gastroenterology 153:550-565|
|Hedl, Matija; Yan, Jie; Abraham, Clara (2016) IRF5 and IRF5 Disease-Risk Variants Increase Glycolysis and Human M1 Macrophage Polarization by Regulating Proximal Signaling and Akt2 Activation. Cell Rep 16:2442-55|
|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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