This proposal is submitted in response to RFA-DK-16-510, ?Limited Competition for the Data Coordinating Center (DCC) for the NIDDK Inflammatory Bowel Disease Genetics Consortium (IBDGC) (U24)?. IBD affects 1.8 to 3 million Americans; better therapies and more rational use of multiple emerging therapies are urgently needed. Over 200 loci have been associated to IBD, prioritizing cells, genes and pathways that drive pathogenesis. The IBDGC, comprised of the DCC and six Genetic Research Centers (GRCs) throughout North America brings together large IBD referral centers to perform well-powered genetic, expression and functional studies. Novel protocols for intestinal sampling and longitudinal follow-up are needed to define precise cellular and molecular mechanisms.
In Aim 1, the DCC will apply new laboratory and computing technologies to collect accurate, detailed data on disease pathogenesis from the clinic all the way down to the cellular level, and to integrate these data with both existing and new genomic data for sharing with the research community. Platforms for longitudinal collections, integration with top collaborating laboratories, and development of new objective assessments of disease activity and responses to treatment are described. The Bionimbus Protected Data Cloud will facilitate collaborative analyses, and data sharing will be enhanced through an IBD Data Commons.
In Aim 2, prioritization of scientific directions and incorporation of new technologies, sampling strategies and analyses is proposed. Key factors include efficiently scaling processes across centers, minimizing and defining analytic and other sources of variation, and longitudinal analyses. Enhancement of credible SNP set definitions will be achieved through increasing power through increased sample sizes of genome-wide association study SNP sets, combining analyses across inflammatory diseases, and integrating more diverse populations. Comprehensive expression analyses of a spheroid collection of inflamed and uninflamed samples derived from ulcerative colitis (UC) patients will define mRNA expression variation driven by genetic variability, thereby defining drivers of UC pathogenesis. Finally, in a large cohort of Crohn's disease patients undergoing ileal resectional surgery, the genetic basis for how pathophysiologic mechanisms function over time will be defined. This large sample set will enable the examination of genetic variation in response to therapeutic interventions and over time. The long-term goal of these studies is to efficiently develop approaches to most effectively treat IBD patients, catalyzing the advent of Precision IBD.

Public Health Relevance

The primary purpose and scientific mission of the NIDDK IBDGC is to identify the causal genes and genetic variants within the known susceptibility loci and to elucidate the roles of risk-associated genetic variants in the pathophysiology of IBD. Essential scientific elements required to fulfill this purpose include large, diverse sample sizes, engagement of new technologies and collaborators and robust computing platforms to facilitate collaboration and data sharing.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Resource-Related Research Projects--Cooperative Agreements (U24)
Project #
5U24DK062429-19
Application #
9567542
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Karp, Robert W
Project Start
2002-09-30
Project End
2022-07-31
Budget Start
2018-09-01
Budget End
2019-07-31
Support Year
19
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Genetics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Li, Dalin; Haritunians, Talin; Landers, Carol et al. (2018) Late-Onset Crohn's Disease Is A Subgroup Distinct in Genetic and Behavioral Risk Factors With UC-Like Characteristics. Inflamm Bowel Dis 24:2413-2422
Rivas, Manuel A; Avila, Brandon E; Koskela, Jukka et al. (2018) Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population. PLoS Genet 14:e1007329
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
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
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
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
Huang, Chengrui; Haritunians, Talin; Okou, David T et al. (2015) Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans. Gastroenterology 149:1575-1586

Showing the most recent 10 out of 14 publications