Journal Article

Association of plasma mitochondrial DNA with COPD severity and progression in the SPIROMICS cohort

Couper, David J., Criner, Gerard J., Schiffer, Kristen T., Curtis, Jeffrey L., Martinez, Fernando J., Labaki, Wassim W., Rice, Michelle C., Nakahira, Kiichi, Woodruff, Prescott G., Hansel, Nadia N., Cloonan, Suzanne M., Diaz, Ivan, Han, Meilan K., Paine, Robert, Barjaktarevic, Igor, Putcha, Nirupama, Hoffman, Katherine L., Wells, J. Michael, Bowler, Russell P., Oromendia, Clara, Peters, Stephen P., Zhang, William Z., Ballman, Karla V., Choi, Mary E., Choi, Augustine M. K.

2021

Overview

Background There 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. Methods P-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. Results P-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. Conclusion In 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)

• Publisher: BioMed Central,BioMed Central Ltd,Nature Publishing Group,BMC
• Subject: Accounting / Aged / Air flow / Biomarkers / Chronic obstructive pulmonary disease / COPD / Copy number / Deoxyribonucleic acid / Development and progression / Disease / Disease Progression / DNA / DNA, Mitochondrial - blood / DNA, Mitochondrial - genetics / Emphysema / Exercise Tolerance / Female / Forced Expiratory Volume / Genetic aspects / Health aspects / Humans / Longitudinal Studies / Lung - physiopathology / Lung diseases / Lung diseases, Obstructive / Male / Medicine / Medicine & Public Health / Middle Aged / Mitochondrial DNA / Mitochondrial dysfunction / Mortality / mtDNA / NADH / NADH dehydrogenase / NADH Dehydrogenase - blood / NADH Dehydrogenase - genetics / Nicotinamide adenine dinucleotide / Obstructive lung disease / Plasma / Pneumology/Respiratory System / Population / Prospective Studies / Pulmonary Disease, Chronic Obstructive - blood / Pulmonary Disease, Chronic Obstructive - diagnosis / Pulmonary Disease, Chronic Obstructive - genetics / Pulmonary Disease, Chronic Obstructive - physiopathology / Severity of Illness Index / Smokers / Smoking / Smoking - adverse effects / Spirometry / SPIROMICS / Subpopulations / Surveys and Questionnaires / Time Factors / United States / Walk Test