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

项目总结

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 mechanistic studies and research into targeted therapies beyond ICS.