Cell-free DNA levels associate with COPD exacerbations and mortality

• Published in: Respiratory research 2024-01, Vol.25 (1), p.42-10, Article 42
• Main Authors: Ware, Sarah A, Kliment, Corrine R, Giordano, Luca, Redding, Kevin M, Rumsey, William L, Bates, Stewart, Zhang, Yingze, Sciurba, Frank C, Nouraie, S Mehdi, Kaufman, Brett A
• Format: Article
• Language: English
• Subjects: Airway management; Automation; Biomarkers; Body mass index; Cell-Free Nucleic Acids - genetics; Chronic obstructive pulmonary disease; Cigarette smoke; Confidence intervals; Copy number; Deoxyribonucleic acid; Development and progression; Disease Progression; DNA; DNA, Mitochondrial; Female; Generalized linear models; Genomes; Health risks; Humans; Hypothesis testing; Leukocytes (eosinophilic); Lung diseases; Lung diseases, Obstructive; Male; Middle Aged; Mitochondrial DNA; Mortality; Mortality risk; Normal distribution; Obstructive lung disease; Pathogenesis; Patient outcomes; Phenotype; Phenotypes; Plasma; Polymerase chain reaction; Pulmonary Disease, Chronic Obstructive - diagnosis; Pulmonary Disease, Chronic Obstructive - genetics; Questions; Regression analysis; Risk; Risk factors; Statistical analysis
• ISSN: 1465-993X; 1465-9921; 1465-993X; 1465-9921
• DOI: 10.1186/s12931-023-02658-1

Good biological indicators capable of predicting chronic obstructive pulmonary disease (COPD) phenotypes and clinical trajectories are lacking. Because nuclear and mitochondrial genomes are damaged and released by cigarette smoke exposure, plasma cell-free mitochondrial and nuclear DNA (cf-mtDNA and cf-nDNA) levels could potentially integrate disease physiology and clinical phenotypes in COPD. This study aimed to determine whether plasma cf-mtDNA and cf-nDNA levels are associated with COPD disease severity, exacerbations, and mortality risk. We quantified mtDNA and nDNA copy numbers in plasma from participants enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE, n = 2,702) study and determined associations with relevant clinical parameters. Of the 2,128 participants with COPD, 65% were male and the median age was 64 (interquartile range, 59-69) years. During the baseline visit, cf-mtDNA levels positively correlated with future exacerbation rates in subjects with mild/moderate and severe disease (Global Initiative for Obstructive Lung Disease [GOLD] I/II and III, respectively) or with high eosinophil count (≥ 300). cf-nDNA positively associated with an increased mortality risk (hazard ratio, 1.33 [95% confidence interval, 1.01-1.74] per each natural log of cf-nDNA copy number). Additional analysis revealed that individuals with low cf-mtDNA and high cf-nDNA abundance further increased the mortality risk (hazard ratio, 1.62 [95% confidence interval, 1.16-2.25] per each natural log of cf-nDNA copy number). Plasma cf-mtDNA and cf-nDNA, when integrated into quantitative clinical measurements, may aid in improving COPD severity and progression assessment.