# NIDDK IBD Genetics Consortium Genetic Research Center

> **NIH NIH U01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $437,300

## Abstract

ABSTRACT
Crohn’s disease and ulcerative colitis, the two major forms of idiopathic inflammatory bowel disease (IBD), are
chronic disorders of the gastrointestinal tract affecting ~3.7 million Americans and Europeans, and several
hundred thousand more worldwide. Intensive searches for genetic risk factors, including genome-wide
association studies (GWAS) and follow-up studies by the NIDDK Inflammatory Bowel Disease Genetics
Consortium and the International Inflammatory Bowel Disease Genetics Consortium have yielded significant
evidence for association between IBD and >240 genetic loci, and have illuminated biological pathways such as
the IL-23/T helper 17 (Th17) immune pathway, autophagy, mucosal barrier function, and immune activation of
multiple integrin genes in IBD pathogenesis. While fine genetic association mapping efforts have resolved 51
association signals to a single genetic variant with >50% probability of being causal, the remaining known IBD
loci have yet to be fine mapped. Access to large patient sample sizes and the multidisciplinary team science that
a consortium facilitates are crucial for the momentum in dissecting the genetics of IBD to continue, and for
bridging the gaps between genetic associations, mechanistic understanding, and improved therapies. Thus, in
Aim 1 of this competitive renewal application we propose to continue our participation in IBDGC research efforts,
and we propose specific consortium-wide projects for consideration by the Steering Committee.
A major challenge in moving from genetic associations to mechanistic understanding is the fact that SNP(s) with
the strongest association signal(s) in most established IBD loci lie in non-coding regions, where our knowledge
of the functional effects of DNA variation pales in contrast to our understanding of the genetic code for amino
acids in protein-coding regions. Additionally, genetic studies alone cannot distinguish causal variants from
neighboring non-causal variants in linkage disequilibrium for many known IBD association signals. Fortunately,
recent studies suggest a way forward. Comparing the locations of non-coding, disease-associated SNPs with
chromatin maps in specific cell types and stimulation conditions can prioritize candidate non-coding DNA
variants, specific cell types and contexts for follow-up functional studies. In Aim 2, we will define the molecular
effects of IBD-associated, non-coding, accessible chromatin region DNA variation on primary human
CD4+CD45RO+CD196(CCR6)+ T cell (a subset including both Th17 and T regulatory [Treg] cells) functional
responses to specific stimulation conditions. This work will build on our mapping of accessible chromatin regions
in CD4+CD45RO+CD196+ T cells stimulated under two specific conditions, our identification of overlap between
these accessible chromatin regions and SNPs in the credible set for each fine mapped IBD locus that is >95%
likely to contain the causal variant, and our preliminary integration of chrom...

## Key facts

- **NIH application ID:** 10001509
- **Project number:** 5U01DK062420-19
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Richard H Duerr
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,300
- **Award type:** 5
- **Project period:** 2002-09-30 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001509

## Citation

> US National Institutes of Health, RePORTER application 10001509, NIDDK IBD Genetics Consortium Genetic Research Center (5U01DK062420-19). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10001509. Licensed CC0.

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