# Defining a gene expression signature of airway disease, COPD exacerbations, and response to treatment

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $815,376

## Abstract

PROJECT SUMMARY
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, with varying contributions of
emphysema and large and small airway disease. COPD heterogeneity is also manifest in variable responses to
treatments, including inhaled corticosteroids (ICS). There is an unmet need for biomarkers for COPD outcomes.
Our group has led RNA-sequencing on blood samples collected at the Phase 2 (5 year) visit in the Genetic
Epidemiology of COPD Study (COPDGene). We found that a type 1 interferon-stimulated gene expression
signature in whole blood was associated with airway measures from quantitative analysis of chest computed
tomography (CT) scans. A score summarizing the expression of these genes was associated with reduced lung
function and COPD exacerbations. The association between the interferon gene score and airway disease was
abolished in ICS users. Our hypothesis is that interferon pathway blood gene expression could be used to define
an endotype of COPD characterized by airway disease, which will serve as a predictive biomarker for COPD
exacerbations and progression and can be targeted with ICS therapy. We will address the following Specific
Aims: (1) Airway-interferon predictor of exacerbations and progression: Using COPDGene Phase 3 (10 year)
clinical and imaging data, we will use the interferon airway gene signature as a biomarker to develop prediction
models for acute exacerbations and disease progression in subjects with and without COPD. The gene signature
prediction will be validated in additional COPD studies. (2) Airway-interferon endotype of COPD: We will perform
RNA-sequencing in blood samples from the COPDGene Phase 3 visit to test for stability vs. change of gene
expression signatures and clinical phenotypes over a five-year interval. To identify lung tissue correlates of the
blood gene expression, we will analyze RNA-seq data in resected lung samples from smokers with and without
COPD from the Lung Tissue Research Consortium (LTRC), testing for associations between interferon signature
genes with chest CT scan-defined airway disease and COPD phenotypes. (3) Response to inhaled
corticosteroids: In COPDGene and LTRC, we will test whether the associations between the interferon gene
signature and COPD phenotypes of airway disease, exacerbations, and lung function decline are altered in ICS
users compared to non-users. We will measure expression of interferon signature genes in a previously
completed 12-week clinical trial of ICS in COPDGene subjects, and test whether ICS use affects the interferon-
stimulated gene expression pattern. We will re-analyze the clinical trial to test whether the interferon signature
predicts response to ICS. This proposal will complement the ongoing analyses in COPDGene by developing a
biomarker for COPD outcomes and targeted ICS prescription, which can be used for a future pharmacogenomics
clinical trial. Understanding the airway disease interferon gene signature can guide future mec...

## Key facts

- **NIH application ID:** 10851951
- **Project number:** 5R01HL166231-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** CRAIG P HERSH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $815,376
- **Award type:** 5
- **Project period:** 2023-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851951

## Citation

> US National Institutes of Health, RePORTER application 10851951, Defining a gene expression signature of airway disease, COPD exacerbations, and response to treatment (5R01HL166231-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10851951. Licensed CC0.

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