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 100 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, led the largest genome wide linkage study in IBD and has led the IBDGC in a focus on African American (AA) IBD genetics (recruiting 88% of study subjects). We published the first large clinical characterization of AA IBD, serological associations of AA CD, clinical disparity studies, and most recently evaluation of admixture in AA CD, NOD2 the other four most well characterized CD genetic loci. More research in AA IBD is needed to understand the etiology of IBD in this ancestrally distinct, major American population, and also because diverse allelic and haplotype structure, and potential for unique functional variants will yield benefits for all populations. Additionally, a major challenge, especially for non- coding associations, is to know which SNPs are causative vs. those in linkage disequilibrium. Comparing association patterns across populations and evaluating function of associated SNPs that map to potential transcription factor (TF) sites active in IBD related cells will be beneficial.
Our Aims i n the next funding period are to (1) facilitate more comprehensive IBD gene discovery and evaluation in the AA population, and (2) to characterize the epigenome relevant to IBD and evaluate the most provocative non-coding SNPs across populations that map to potential TF binding sites for alterning genomic function. For the first Aim, we have enlarged our recruitment to12 satellite recruitment centers and will recruit 1000 AA IBD cases (with potential of 2600 cases) over the next five years. Immunochip IBD genotyping in AA's and a first stage AA CD GWAS IBD are underway, with facilitation of a 2nd stage ancillary R01 AA CD GWAS with Emory University planned for Year 3. We will perform an IBDGC AA UC GWAS of 1000 cases in year 4. We will compare IBD associations across ethnic groups to define most consistent non-coding SNPs.
For Aim 2, we've assembled a team to help us characterize IBD relevant epigenomic annotation. We will purify immune cells from resected colon of patients, perform ChIP-Seq, and evaluate SNPs that map to TF binding sites using in-vitro enhancer assays in transfected cell lines. We will play a major role in all IBDGC activities, with our team of genetic statistical, genomic, immunology, and microbiome co-investigators, by our ability to obtain biological materials (including blood, biopsy, resection, and stool) and to recall patients for re-sampling, and by working cooperatively to maximize productivity of the IBDGC and its GRCs and DCC.

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 #
5U01DK062431-12
Application #
8549198
Study Section
Special Emphasis Panel (ZDK1-GRB-G (O3))
Program Officer
Karp, Robert W
Project Start
2002-09-30
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
12
Fiscal Year
2013
Total Cost
$409,831
Indirect Cost
$156,849
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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McGovern, Dermot P B; Gardet, Agnes; Torkvist, Leif et al. (2010) Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet 42:332-7
Franke, Andre; McGovern, Dermot P B; Barrett, Jeffrey C et al. (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 42:1118-25
Dassopoulos, Themistocles; Nguyen, Geoffrey C; Talor, Monica Vladut et al. (2010) NOD2 mutations and anti-Saccharomyces cerevisiae antibodies are risk factors for Crohn's disease in African Americans. Am J Gastroenterol 105:378-86
Nguyen, Geoffrey C; LaVeist, Thomas A; Harris, Mary L et al. (2010) Racial disparities in utilization of specialist care and medications in inflammatory bowel disease. Am J Gastroenterol 105:2202-8

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