# Genomics of Inflammatory Bowel Disease

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $770,629

## Abstract

In Inflammatory Bowel Disease (EBV) Epstein-Barr virus (EBV) infection is thought to contribute to disease
severity and resistance to therapy. Recently, we discovered a powerful association between the DNA
immunoprecipitated by EBNA2 and the risk loci of IBD, intersecting 38 of 112 evaluated loci (from the GWAS
catalog in 2015) (RR=3.3, Pc=1.24x10-13) (1). Newer data confirm the EBNA2 association and also show that
EBNA3C and EBNALP ChIP-seq (chromatin immunoprecipitation with next generation sequencing) data are
also associated with IBD loci (RR=2.3, Pc=2.3x10-12 & RR=2.3, Pc=2.3x10-12, respectively) while BZLF1 (ZTA),
an EBV Lytic program transcription factor (TF), is not associated. EBNA2, EBNA3C, and EBNALP are expressed
in the EBV Latency III program of viral gene expression, causing the infected B cell to transform and becoming
a major target for incomplete destruction by the normal human immune system. Interestingly, human
transcription factors (TFs) tend to bind the same loci that are bound by these Latency III EBV gene products,
forming intersection clusters that identify the contributing, presumably, regulatory IBD loci. Our interpretation is
that these associations strongly suggest that at the intersecting loci viral mechanisms commandeering the
cellular phenotype are shared with the genetic mechanisms of IBD risk. We conclude that this relationship likely
represents related molecular pathways. The question is whether these associations are correlations, reflecting
converging but independent mechanisms, or whether these correlations are interdependent and exist because
the virus is etiologic and involved in disease pathogenesis. Establishing either possibility would be a major
advance for IBD with viral constituents being probes to dissect mechanism. If EBV infection is etiologic, then,
perhaps, the initial EBV-related lesion interferes with the barrier function, allowing the endogenous microbiome
to induce the inflammatory response that we recognize as one or more of the pathologies of IBD. Since other
EBNA2 associated disorders are autoimmune (1) and some EBV associations with IBD severity are colonic, if
EBV is etiologic, then the autoimmunity of Ulcerative Colitis (UC) would be a most likely suspect.
We propose to: Aim 1.) Exploit the discovery of additional IBD risk loci; improvements in our informatics,
including allele specific analysis; and the new chromatin immunoprecipitation data accumulated to redefine the
associations previously discovered (1). Aim 2.) Better understand the genomic mechanisms of IBD by applying
state-of-the-art genomic technologies. Aim 3.) Develop new therapeutics for IBD directed against EBV,
particularly against the Latency III transforming expression program of EBV, and Aim 4.) Test the prediction of
the etiologic possibility that EBV-infection is increased in IBD and, if so, then identify the characteristics of the
IBD subset whose illness is related to the inflammatory pathology of IBD, perhaps those...

## Key facts

- **NIH application ID:** 10242842
- **Project number:** 5R01AI148276-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Leah Claire Kottyan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $770,629
- **Award type:** 5
- **Project period:** 2019-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242842

## Citation

> US National Institutes of Health, RePORTER application 10242842, Genomics of Inflammatory Bowel Disease (5R01AI148276-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242842. Licensed CC0.

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