This application from the Mount Sinai Health System proposes participation as a genetic research center (GRC) within the NIDDK Inflammatory Bowel Disease Genetics Consortium (IBDGC). IBD genetic discovery has disproportionately focused on European ancestry cohorts, despite high and rising prevalence in all US populations.
In Aim 1, participation as a multi- disciplinary GRC in Consortium-wide projects is proposed. Expanding sequence and genotype data on non-European ancestry cohorts is proposed. New analytic methodologies have been developed whereby more ancestrally complex populations, such as Hispanic cohorts, can not only be meaningfully analyzed, but may confer substantial benefits in unlocking the overall genetic architecture of polygenic diseases, such as IBD. The application of novel clinical research tools involving efficient electronic health record and development of more objective endpoints can deepen longitudinal phenotype data for already recruited patients. Given the continued centrality of anti-TNF therapies in an era of multiple new therapies, studies to examine anti-TNF non-response (ileal resection, surgical specimens) and response (new anti- TNF initiation, endoscopically-based) are proposed. Specifically, in Aim 2, definition of intestinal single-cell expression features with anti-TNF non-response and response is proposed using mass cytometry protein analyses (Cytof), and single cell mRNA sequencing. Single cell analyses in IBD tissues shows enormous promise in systematically explicating the precise contributions in the most relevant context of the over 200 genome-wide significant IBD associations. Early single cell analyses points to a highly complex innate immune cell architecture, which may be distinct between various high effect IBD-associated risk alleles of innate immunity. Scaling key results through correlative techniques feasible in larger cohorts, such as using paraffin-embedded tissues and peripheral blood samples is proposed. The advent of multiple new therapies makes this a particularly propitious time to protocolize clinical practice, both to improve patient care, as well as to mine biosamples for IBD research. The insight that is gained through these studies can prioritize genes, cells and pathways from which to scale key results and protocols across the NIDDK IBDGC. The long-term goal of these studies is to efficiently develop protocols to most effectively treat IBD patients, catalyzing the advent of Precision IBD.

Public Health Relevance

Genetic discovery in inflammatory bowel disease (IBD) has identified disease-associated genes, some of which have and will be developed as new therapeutic targets. Defining IBD-associated gene expression at the single cell level, in the context of ineffective and effective medical therapies, has the potential to define which therapies at which time will be most effective in which patients with IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01DK062422-18
Application #
9402373
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Karp, Robert W
Project Start
2002-09-30
Project End
2022-08-31
Budget Start
2017-09-30
Budget End
2018-08-31
Support Year
18
Fiscal Year
2017
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
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; Proctor, Deborah D; Abraham, Clara (2016) JAK2 Disease-Risk Variants Are Gain of Function and JAK Signaling Threshold Determines Innate Receptor-Induced Proinflammatory Cytokine Secretion in Macrophages. J Immunol 197:3695-3704
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

Showing the most recent 10 out of 85 publications