# Functional outcomes of inflammatory bowel disease associated variants

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $563,028

## Abstract

Project Summary/Abstract
The interplay between microbial and genetic susceptibility factors is central to the development of
inflammatory bowel disease (IBD). Innate mechanisms, in particular through pattern recognition receptor
(PRR) pathways, are the initiating drivers of host responses to microbes. Of the 200 loci associated to
IBD, a number of genes modulate host PRR responses at many levels, and confer some of the largest
genetic effect sizes observed in autoimmunity. Despite the significant recent discoveries in IBD-
associated genetic loci, the functional consequences of the majority of these loci have yet to be identified.
A central outcome of PRR activation by microbial products is induction of cytokines and microbial
clearance pathways. IBD is largely characterized by dysregulated cytokines and anti-microbial
responses, and modulation of cytokines plays a primary role in IBD treatment. Inter-individual variation in
PRR-induced outcomes influences the critical balance between susceptibility to infection and
inflammatory diseases. We hypothesize that polymorphisms in multiple IBD-associated genes contribute
to inter-individual variation in PRR-induced cytokine secretion and microbial clearance pathways.
Systematic, well-powered studies comprehensively defining the functional alterations driven by disease-
associated human variation can provide enormous insight into central mechanisms of IBD; leveraging
naturally occurring human genetic variation to systematically “perturb” an experimental system represents
an advantageous approach for precisely defining established and novel PRR-mediated mechanisms of
signaling, cytokine secretion and microbial clearance. Therefore, we will utilize a large, well-powered
cohort to screen for IBD-associated polymorphisms contributing to the variation in PRR-initiated cytokine
secretion across individuals, and then define the molecular mechanisms wherein the implicated IBD-
associated genes, as well as the identified polymorphisms, regulate PRR-induced signaling, cytokine
secretion, and microbial clearance pathways.
Relevance
These combined studies will provide insight into whether those IBD-associated loci that regulate PRR-
induced signaling, cytokine secretion and bacterial clearance do so through a loss- or gain-of-function, the
mechanisms wherein the implicated genes mediate their contributions to these PRR-induced outcomes,
and the specific consequences of the polymorphisms on gene function through examination of monocyte-
derived cells from selected carriers. These comprehensive and mechanistic studies will be crucial for
future studies that will examine gene consequences in vivo and ultimately, in the context of disease
targeting.

## Key facts

- **NIH application ID:** 10321645
- **Project number:** 5R01DK099097-09
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** CLARA ABRAHAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $563,028
- **Award type:** 5
- **Project period:** 2013-09-18 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10321645

## Citation

> US National Institutes of Health, RePORTER application 10321645, Functional outcomes of inflammatory bowel disease associated variants (5R01DK099097-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10321645. Licensed CC0.

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