Abstract
BackgroundThere is a lack of mechanism-driven, clinically relevant biomarkers in chronic obstructive pulmonary disease (COPD). Mitochondrial dysfunction, a proposed disease mechanism in COPD, is associated with the release of mitochondrial DNA (mtDNA), but plasma cell-free mtDNA has not been previously examined prospectively for associations with clinical COPD measures.MethodsP-mtDNA, defined as copy number of mitochondrially-encoded NADH dehydrogenase-1 (MT-ND1) gene, was measured by real-time quantitative PCR in 700 plasma samples from participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Associations between p-mtDNA and clinical disease parameters were examined, adjusting for age, sex, smoking status, and for informative loss to follow-up.ResultsP-mtDNA levels were higher in participants with mild or moderate COPD, compared to smokers without airflow obstruction, and to participants with severe COPD. Baseline increased p-mtDNA levels were associated with better CAT scores in female smokers without airflow obstruction and female participants with mild or moderate COPD on 1-year follow-up, but worse 6MWD in females with severe COPD. Higher p-mtDNA levels were associated with better 6MWD in male participants with severe COPD. These associations were no longer significant after adjusting for informative loss to follow-up.ConclusionIn this study, p-mtDNA levels associated with baseline COPD status but not future changes in clinical COPD measures after accounting for informative loss to follow-up. To better characterize mitochondrial dysfunction as a potential COPD endotype, these results should be confirmed and validated in future studies.Trial Registration: ClinicalTrials.gov NCT01969344 (SPIROMICS)
Highlights
Chronic obstructive pulmonary disease (COPD) is a chronic lung disease that is defined by airflow limitation on spirometry and persistent respiratory symptoms and is a leading cause of morbidity and mortality worldwide [1, 2]
We examined whether plasma mitochondrial DNA (mtDNA) (p-mtDNA) measured at baseline correlated with post-bronchodilator FEV1% predicted, 6-min walk distance (6MWD), St. George’s Respiratory Questionnaire (SGRQ), chronic obstructive pulmonary disease (COPD) Assessment Test (CAT), and % emphysema measured at baseline using Pearson’s correlation coefficients and Pearson’s partial correlation coefficients holding age, sex, and current smoking status constant
Samples were randomly selected, compared to the overall SPIROMICS population, the p-mtDNA study population was over-represented by non-smokers and participants with severe COPD, and under-represented in participants with mild or moderate COPD (p < 0.001, Additional file 1: Table 1); the study population was less likely to be currently smoking compared to the overall SPIROMICS cohort (p = 0.002)
Summary
Chronic obstructive pulmonary disease (COPD) is a chronic lung disease that is defined by airflow limitation on spirometry and persistent respiratory symptoms and is a leading cause of morbidity and mortality worldwide [1, 2]. Among the relevant proposed mechanisms is mitochondrial dysfunction, with supporting evidence from both COPD patients [8,9,10,11,12,13,14] and experimental COPD models [15,16,17,18] This dysfunction, partly attributed to mitochondrial oxidative stress [12] and manifested differently in different cell types, is often accompanied by the release of mitochondrial DNA (mtDNA) into the cytosol and extracellular space [19]. Mitochondrial dysfunction, a proposed disease mechanism in COPD, is associated with the release of mitochondrial DNA (mtDNA), but plasma cell-free mtDNA has not been previously examined prospectively for associations with clinical COPD measures
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