Min Hyung Ryu, PhD
Channing Division of Network Medicine
Min Hyung Ryu*, Jeong H. Yun, Jarrett D. Morrow, Aabida Saferali, Peter Castaldi, Robert Chase, Meryl Stav, Zhonghui Xu, Igor Barjaktarevic, MeiLan Han, Wassim Labaki, Yvonne J. Huang, Stephanie Christenson, Wanda O’Neal, Russell Bowler, Don D. Sin, Christine M. Freeman, Jeffrey L. Curtis, Craig P. Hersh
Craig P. Hersh
Rationale: Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) are associated with a significant disease burden. Blood immune phenotyping may improve our understanding of a COPD endotype at increased risk of exacerbations.
Objective: To determine the relationship between the transcriptome of circulating leukocytes and COPD exacerbations.
Methods: Blood RNA sequencing data (n=3618) from the COPDGene study were analyzed. Blood microarray data (n=646) from the ECLIPSE study were used for validation. We tested the association between blood gene expression and AE-COPD. We imputed the abundance of leukocyte subtypes and tested their association with prospective AE-COPD. Flow cytometry was performed on blood in SPIROMICS (n=127), and activation markers for T cells were tested for the association with prospective AE-COPD.
Measurements and Main Results: Exacerbations were reported 4030 and 2368 times during the follow-up in COPDGene (5.31.7 years) and ECLIPSE (3 years), respectively. We identified 890, 675, and 3217 genes associated with a history of AE-COPD, persistent exacerbations (1 exacerbation per year), and prospective exacerbation rate, respectively. In COPDGene, the number of prospective exacerbations in COPD subjects (GOLD ≥2) was negatively associated with circulating CD8+ T cells, CD4+ T cells, and resting NK cells. The negative association with naïve CD4+ T cells was replicated in ECLIPSE. In the flow cytometry study, an increase in CTLA4 on CD4+ T cells was positively associated with AE-COPD.
Conclusions: Individuals with COPD having lower circulating lymphocytes, particularly decreased CD4+ T cells, are more susceptible to AE-COPD, including persistent exacerbations.
Our transcriptomics-based investigation provides robust data unveiling the relationship between blood-based molecular and cellular phenotypes with chronic obstructive pulmonary disease (COPD) exacerbations, an important clinical endpoint. Our work highlights that individuals with COPD having lower circulating lymphocytes, particularly decreased CD4+ T cells, are more susceptible to acute exacerbation of COPD, including persistent exacerbations.
We also found cell-type-specific gene expression in neutrophils and CD4+ T cells that were associated with prospective COPD exacerbations. Our study provides important molecular insight into exacerbation-susceptible endotype. Defining and understanding an exacerbation-susceptible endotype holds great potential to be translated into tools for improving clinical trials for new therapies and to be used in the long-term management of COPD. Our findings support that circulating immune cells, specifically neutrophils and CD4+ T cells, and their gene expression may be a potential biomarker for acute exacerbation of COPD, but further research and validation are needed.