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

doi:10.1186/s12931-021-01707-x

Observational Study

. 2021 Apr 26;22(1):126.

doi: 10.1186/s12931-021-01707-x.

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

William Z Zhang^{1

2}, Katherine L Hoffman³, Kristen T Schiffer¹, Clara Oromendia³, Michelle C Rice⁴, Igor Barjaktarevic⁵, Stephen P Peters⁶, Nirupama Putcha⁷, Russell P Bowler⁸, J Michael Wells⁹, David J Couper¹⁰, Wassim W Labaki¹¹, Jeffrey L Curtis¹¹, Meilan K Han¹¹, Robert Paine 3rd¹², Prescott G Woodruff¹³, Gerard J Criner¹⁴, Nadia N Hansel⁷, Ivan Diaz³, Karla V Ballman³, Kiichi Nakahira¹, Mary E Choi^{2

4}, Fernando J Martinez^{1

2}, Augustine M K Choi^{1

2}, Suzanne M Cloonan^{15

16

17}

Affiliations

¹ Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
² Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY, USA.
³ Department of Population Health Science, Division of Biostatistics and Epidemiology, Weill Cornell Medicine, New York, NY, USA.
⁴ Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
⁵ Division of Pulmonary and Critical Care Medicine, University of California Los Angeles Medical Center, Los Angeles, CA, USA.
⁶ Pulmonary, Critical Care, Allergy, and Immunologic Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁷ Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USA.
⁹ University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁰ Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, MI, USA.
¹² Section of Pulmonary and Critical Care Medicine, Salt Lake City Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA.
¹³ University of California at San Francisco, San Francisco, CA, USA.
¹⁴ Department of Pulmonary & Critical Care Medicine, Temple University, Philadelphia, PA, USA.
¹⁵ Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA. szc2009@med.cornell.edu.
¹⁶ School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland and Tallaght University Hospital, Dublin, Ireland. szc2009@med.cornell.edu.
¹⁷ Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, USA. szc2009@med.cornell.edu.

PMID: 33902556
PMCID: PMC8074408
DOI: 10.1186/s12931-021-01707-x

Observational Study

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

William Z Zhang et al. Respir Res. 2021.

. 2021 Apr 26;22(1):126.

doi: 10.1186/s12931-021-01707-x.

Authors

Affiliations

¹ Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
² Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY, USA.
³ Department of Population Health Science, Division of Biostatistics and Epidemiology, Weill Cornell Medicine, New York, NY, USA.
⁴ Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
⁵ Division of Pulmonary and Critical Care Medicine, University of California Los Angeles Medical Center, Los Angeles, CA, USA.
⁶ Pulmonary, Critical Care, Allergy, and Immunologic Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁷ Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USA.
⁹ University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁰ Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, MI, USA.
¹² Section of Pulmonary and Critical Care Medicine, Salt Lake City Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA.
¹³ University of California at San Francisco, San Francisco, CA, USA.
¹⁴ Department of Pulmonary & Critical Care Medicine, Temple University, Philadelphia, PA, USA.
¹⁵ Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA. szc2009@med.cornell.edu.
¹⁶ School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland and Tallaght University Hospital, Dublin, Ireland. szc2009@med.cornell.edu.
¹⁷ Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, USA. szc2009@med.cornell.edu.

PMID: 33902556
PMCID: PMC8074408
DOI: 10.1186/s12931-021-01707-x

Abstract

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).

Keywords: COPD; Mitochondrial dysfunction; SPIROMICS; mtDNA.

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Conflict of interest statement

IB reports grants from NHLBI, during the conduct of the study; grants and personal fees from Theravance and Mylan, grants from Amgen, personal fees from Astra Zeneca, personal fees from GSK, personal fees from Boehringer Ingelheim, personal fees from Verona Pharma, personal fees from Grifols, outside the submitted work. AMKC is a cofounder, stockholder, and serves on the Scientific Advisory Board for Proterris, which develops therapeutic uses for carbon monoxide. A.M.K.C. also has a use patent on CO. A.M.K.C. served as a consultant for Teva Pharmaceuticals in July 2018. MEC reports grants from NIH, during the conduct of the study. DJC reports grants from NHLBI, grants from COPD Foundation, during the conduct of the study. GJC reports grants and personal fees from Galaxo Smith Kline, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Chiesi, grants and personal fees from Mereo, personal fees from Verona, grants and personal fees from Astra Zeneca, grants and personal fees from Pulmonx, grants and personal fees from Pneumrx, personal fees from BTG, grants and personal fees from Olympus, grants and personal fees from Broncus, personal fees from EOLO, personal fees from NGM, grants and personal fees from Lungpacer, grants from Alung, grants and personal fees from Nuvaira, grants and personal fees from ResMed, grants and personal fees from Respironics, grants from Fisher Paykel, grants and personal fees from Patara, grants from Galapgos, outside the submitted work. JLC reports a grant from NIH/NHLBI during the conduct of the study; grants from NIH/NHLBI, NIH/NIAID, the Department of Veterans Affairs, and the Department of Defense, outside the submitted work; and personal fees from AstraZeneca, Ltd. and Novartis AG, outside the submitted work. MKH reports grants from NHLBI, during the conduct of the study; personal fees from GlaxoSmithKline, personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, personal fees from Merck, personal fees from Mylan, other from Sunovion, other from Novartis, outside the submitted work. NHH reports grants and personal fees from AstraZeneca, grants from Boehringer Ingelheim, grants from NIH, grants from COPD Foundation, personal fees from Mylan, outside the submitted work. WWL reports grants from National Institutes of Health, non-financial support from Pulmonx, personal fees from Konica Minolta, outside the submitted work. FJM reports personal fees and non-financial support from American College of Chest Physicians, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Boehringer Ingelheim, non-financial support from ProterrixBio, personal fees from Columbia University, personal fees and non-financial support from ConCert, personal fees and non-financial support from Genentech, personal fees and non-financial support from GlaxoSmithKline, personal fees and non-financial support from Inova Fairfax Health System, personal fees from Integritas, personal fees from MD Magazine, personal fees from Methodist Hospital Brooklyn, personal fees and non-financial support from Miller Communicatinos, personal fees and non-financial support from National Association for Continuing Education, personal fees and non-financial support from Novartis, personal fees from New York University, personal fees and non-financial support from Pearl Pharmaceuticals, personal fees and non-financial support from PeerView Communications, personal fees and non-financial support from Prime Communications, personal fees and non-financial support from Puerto Rican Respiratory Society, personal fees and non-financial support from Chiesi, personal fees and non-financial support from Sunovion, personal fees and non-financial support from Theravance, personal fees from UpToDate, personal fees from WebMD/MedScape, personal fees from Western Connecticut Health Network, other from Afferent/Merck, non-financial support from Gilead, non-financial support from Nitto, personal fees from Patara/Respivant, personal fees from PlatformIQ, personal fees and non-financial support from Potomac, other from Biogen, personal fees and non-financial support from University of Alabama Birmingham, other from Veracyte, non-financial support from Zambon, personal fees from American Thoracic Society, grants from NIH, personal fees and non-financial support from Physicians Education Resource, personal fees from Rockpointe, other from Prometic, personal fees from Rare Disease Healthcare Communications, other from Bayer, other from Bridge Biotherapeutics, personal fees and non-financial support from Canadian Respiratory Network, other from ProMedior, personal fees and non-financial support from Teva, personal fees from France Foundation, personal fees and non-financial support from Dartmouth, outside the submitted work. RP reports grants from NHLBI, grants from COPD Foundation, during the conduct of the study; grants from US Department of Veterans Affairs, outside the submitted work. SPP reports personal fees from AstraZeneca, personal fees from Novartis, personal fees from TEVA, personal fees from Wolters Kluwer—UpToDate, personal fees from Palladian Partners, NIAID, personal fees from Syneos Health, personal fees from Syneos Health, personal fees from Genentech, personal fees from GSK, personal fees from Integrity CE, personal fees from Respiratory Medicine—Elsevier, outside the submitted work. NP reports grants from NIH, during the conduct of the study. JMW reports grants from NIH/NHLBI, during the conduct of the study; grants from NIH/NCATS, grants from NIH/NHLBI, grants from Vertex Pharmaceuticals, Inc, grants from Bayer AG, grants from ARCUS-MED, LLC, grants from Mereo BioPharma, other from AstraZeneca, other from GlaxoSmithKline, other from Boehringer Ingelheim, other from Takeda, outside the submitted work. PGW reports grants from NIH, during the conduct of the study; personal fees from Sanofi, personal fees from Regeneron, personal fees from Glenmark, personal fees from Theravance, personal fees from GSK, personal fees from NGM Pharma, personal fees from Genentech, outside the submitted work. All other authors report no competing interests.

Figures

**Fig. 1**
Flow diagram for the participants in the SPIROMICS Plasma mtDNA study. COPD, chronic obstructive pulmonary disease

**Fig. 2**
Plasma mtDNA levels were higher in subjects with mild/moderate COPD but falls in severe disease. P-mtDNA was measured in SPIROMICS participants, including never smokers (n = 100; red), smokers without airflow obstruction (n = 199; green), participants with mild/moderate COPD (n = 201; blue), and severe COPD (n = 200; purple). Data are presented as median with box indicating upper and lower quartiles, whiskers indicating extrema, and with p-values calculated by Tukey’s range test

**Fig. 3**
Illustrative example of informative missingness. A simulated correlation between p-mtDNA levels and FEV₁% predicted in the true population (a) in the hypothetical, ideal situation where all participants had complete follow-up (b) in the hypothetical, more likely situation where patients with worse FEV₁% were also less likely to have complete follow-up. Black dots represent complete cases, red dots indicate cases lost to follow-up

See this image and copyright information in PMC

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References

1. GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med. 2017;5(9):691–706. - PMC - PubMed
1. Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD executive summary. Am J Respir Crit Care Med. 2017;195(5):557–82. - PubMed
1. Ford ES, Mannino DM, Wheaton AG, Giles WH, Presley-Cantrell L, Croft JB. Trends in the prevalence of obstructive and restrictive lung function among adults in the United States: findings from the National Health and Nutrition Examination surveys from 1988–1994 to 2007–2010. Chest. 2013;143(5):1395–1406. doi: 10.1378/chest.12-1135. - DOI - PMC - PubMed
1. Agusti A, Hogg JC. Update on the pathogenesis of chronic obstructive pulmonary disease. N Engl J Med. 2019;381(13):1248–1256. doi: 10.1056/NEJMra1900475. - DOI - PubMed
1. Keene JD, Jacobson S, Kechris K, et al. Biomarkers predictive of exacerbations in the SPIROMICS and COPDGene Cohorts. Am J Respir Crit Care Med. 2017;195(4):473–481. doi: 10.1164/rccm.201607-1330OC. - DOI - PMC - PubMed

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[1] GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med. 2017;5(9):691–706. - PMC - PubMed

[2] GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med. 2017;5(9):691–706. - PMC - PubMed

[3] Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD executive summary. Am J Respir Crit Care Med. 2017;195(5):557–82. - PubMed

[4] Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD executive summary. Am J Respir Crit Care Med. 2017;195(5):557–82. - PubMed

[5] Ford ES, Mannino DM, Wheaton AG, Giles WH, Presley-Cantrell L, Croft JB. Trends in the prevalence of obstructive and restrictive lung function among adults in the United States: findings from the National Health and Nutrition Examination surveys from 1988–1994 to 2007–2010. Chest. 2013;143(5):1395–1406. doi: 10.1378/chest.12-1135. - DOI - PMC - PubMed

[6] Ford ES, Mannino DM, Wheaton AG, Giles WH, Presley-Cantrell L, Croft JB. Trends in the prevalence of obstructive and restrictive lung function among adults in the United States: findings from the National Health and Nutrition Examination surveys from 1988–1994 to 2007–2010. Chest. 2013;143(5):1395–1406. doi: 10.1378/chest.12-1135. - DOI - PMC - PubMed

[7] Agusti A, Hogg JC. Update on the pathogenesis of chronic obstructive pulmonary disease. N Engl J Med. 2019;381(13):1248–1256. doi: 10.1056/NEJMra1900475. - DOI - PubMed

[8] Agusti A, Hogg JC. Update on the pathogenesis of chronic obstructive pulmonary disease. N Engl J Med. 2019;381(13):1248–1256. doi: 10.1056/NEJMra1900475. - DOI - PubMed

[9] Keene JD, Jacobson S, Kechris K, et al. Biomarkers predictive of exacerbations in the SPIROMICS and COPDGene Cohorts. Am J Respir Crit Care Med. 2017;195(4):473–481. doi: 10.1164/rccm.201607-1330OC. - DOI - PMC - PubMed

[10] Keene JD, Jacobson S, Kechris K, et al. Biomarkers predictive of exacerbations in the SPIROMICS and COPDGene Cohorts. Am J Respir Crit Care Med. 2017;195(4):473–481. doi: 10.1164/rccm.201607-1330OC. - DOI - PMC - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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