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

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