# Gene-environment interaction pathways in rheumatoid arthritis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $518,188

## Abstract

ABSTRACT
Shared epitope (SE)-coding HLA-DRB1 alleles confer the single strongest genetic risk for severe RA. In
addition to genetic predisposition, exposure to environmental pollutants, such as dioxin-like compounds, and
tobacco smoke strongly affect RA risk and severity. Furthermore, interactions between SE and tobacco smoke
exposure has been shown to increase the risk for RA in a multiplicative, dose-dependent fashion. The
mechanistic basis of this epidemiologically observed gene-environment interaction is unknown.
We have recently uncovered an NF-kB-mediated crosstalk between the SE and aryl hydrocarbon receptor
(AhR) pathways that lead to synergistic effects on osteoclast differentiation and Th17 polarization in vitro.
Administration of AhR pathway agonists to transgenic mice carrying human SE-coding alleles resulted in a
robust increase in arthritis severity, bone destruction and overabundance of osteoclasts and IL17-expressing
cells in the inflamed joints and draining lymph nodes of arthritic mice. Thus, we have uncovered a previously
unrecognized mechanism of gene-environment interaction.
The studies proposed here will focused on detailed characterization of the newly uncovered synergism by
defining the transcriptomic effects of the SE ligand, AhR agonists, and their combination. The physiologic
relevance of the findings will be corroborated in in vivo mouse systems, as well as by human translational
studies. The proposed research will have the following specific aims:
  To identify and map the synergistic pathways using an RNA-seq approach
  To determine the effect of the interaction on chromatin accessibility and validate transcription factor
activation
  To validate interacting pathways in mice exposed to AhR agonists
  To determine pathway interactions in human cell lines and primary cells
When successfully completed, the proposed project will have identified new pathogenic mechanisms and
disease risk and severity markers in RA. Such findings will open the door to identification of new
therapeutic targets that could be pursued in future research projects.

## Key facts

- **NIH application ID:** 10129901
- **Project number:** 5R01AR074930-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Joseph Holoshitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $518,188
- **Award type:** 5
- **Project period:** 2019-04-09 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129901

## Citation

> US National Institutes of Health, RePORTER application 10129901, Gene-environment interaction pathways in rheumatoid arthritis (5R01AR074930-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10129901. Licensed CC0.

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