Inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are complex genetic disorders of the gastrointestinal tract, and a major health burden to patients and society. Tremendous progress has been made in dissecting IBD genetic etiology with identification of over 200 IBD loci by genome wide association studies (GWAS) but mainly limited to persons of European ancestry. The IBD Genetics Consortium (IBDGC) was established to facilitate multicenter collaborative studies of 6 Genetics Research Centers (GRCs) organized with a Data Coordinating Center (DCC). Our GRC at Johns Hopkins (JHGRC) has contributed to all IBDGC studies, meeting recruitment objectives and taking roles in IBDGC leadership positions. Our particular focus is on African American (AA) IBD genetics. We performed the first large-scale evaluation of European loci in the AA population, replicating several genes, but also finding unique African-ancestral variants within these loci, as well as identified multiple admixture significant loci. We also published the first AA IBD genome-wide association study (GWAS), a collaborative effort that identified two African-specific gene loci, and replicated multiple additional European loci. We have also explored why some loci with proven risk variants in Europeans and other populations only cause disease in one ancestral population but not others. More research in AA IBD is needed to understand the etiology of IBD in this ancestrally distinct, major American population. In this application we will re-evaluate the AA GWAS by better imputation, evaluate whole genome sequencing data to test low frequency and rare variants, and perform an evaluation for chromosome X variants. We will recruit a large number of AA IBD patients through our own and multiple Satellite Recruitment Centers to power a second AA IBD GWAS, both UC and CD, and meta-analyze with the first to identify more novel loci, identify more African specific risk variants, and replicate known loci for this population and replicate our admixture loci. We will also incorporate diverse data sources to incorporate into our GWAS analyses including RNA-Seq currently being generated on lymophoblastoid cell lines from AA CD cases and controls, and RNA-Seq that we will generate in colonic biopsies from UC cases and controls. We will evaluate chromatin differences and expression of genes in cell types relevant to IBD from European, AA and East Asian ancestries in an effort to better understand locus heterogeneity by ancestry. We will continue to participate in all IBDGC activities to maximize the Impact of IBD genetics research by this cooperative funding mechanism.

Public Health Relevance

According to the Center for Disease Control and Prevention, an estimated 1.4 million Americans suffer from Inflammatory Bowel Disease (IBD), a chronic debilitating disorder with no cure that includes Crohn's disease and ulcerative colitis. IBD ranks in the top 5 in prevalence for gastrointestinal disorders and represents a significant financial burden to society requiring a lifetime of medical care. This proposed research aims to determine the genetic variations that cause IBD which will aid in developing preventive measures, improving the quality of care with better treatments and educating patients through genetic counseling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK062431-19
Application #
10001511
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Perrin, Peter J
Project Start
2002-09-30
Project End
2022-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
19
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Rbhs-Robert Wood Johnson Medical School
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078795875
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
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Momozawa, Yukihide; Dmitrieva, Julia; Théâtre, Emilie et al. (2018) IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. Nat Commun 9:2427
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
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Huang, Chengrui; De Ravin, Suk See; Paul, Adam R et al. (2016) Genetic Risk for Inflammatory Bowel Disease Is a Determinant of Crohn's Disease Development in Chronic Granulomatous Disease. Inflamm Bowel Dis 22:2794-2801
Sasaki, Mark M; Skol, Andrew D; Hungate, Eric A et al. (2016) Whole-exome Sequence Analysis Implicates Rare Il17REL Variants in Familial and Sporadic Inflammatory Bowel Disease. Inflamm Bowel Dis 22:20-7

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