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
Original language | English (US) |
---|---|
Article number | 126 |
Journal | Respiratory Research |
Volume | 22 |
Issue number | 1 |
DOIs | |
State | Published - Apr 26 2021 |
Keywords
- COPD
- Mitochondrial dysfunction
- SPIROMICS
- mtDNA
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
Fingerprint
Dive into the research topics of 'Association of plasma mitochondrial DNA with COPD severity and progression in the SPIROMICS cohort'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
Association of plasma mitochondrial DNA with COPD severity and progression in the SPIROMICS cohort. / Zhang, William Z.; Hoffman, Katherine L.; Schiffer, Kristen T. et al.
In: Respiratory Research, Vol. 22, No. 1, 126, 26.04.2021.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Association of plasma mitochondrial DNA with COPD severity and progression in the SPIROMICS cohort
AU - Zhang, William Z.
AU - Hoffman, Katherine L.
AU - Schiffer, Kristen T.
AU - Oromendia, Clara
AU - Rice, Michelle C.
AU - Barjaktarevic, Igor
AU - Peters, Stephen P.
AU - Putcha, Nirupama
AU - Bowler, Russell P.
AU - Wells, J. Michael
AU - Couper, David J.
AU - Labaki, Wassim W.
AU - Curtis, Jeffrey L.
AU - Han, Meilan K.
AU - Paine, Robert
AU - Woodruff, Prescott G.
AU - Criner, Gerard J.
AU - Hansel, Nadia N.
AU - Diaz, Ivan
AU - Ballman, Karla V.
AU - Nakahira, Kiichi
AU - Choi, Mary E.
AU - Martinez, Fernando J.
AU - Choi, Augustine M.K.
AU - Cloonan, Suzanne M.
N1 - Funding Information: 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. Funding Information: This work was supported by National Institutes of Health grants P01 HL114501 (A.M.K.C.), R01 HL132198 (A.M.K.C. and M.E.C.), R00 HL125899 (S.M.C), KL2-TR-002385 (K.N.), U01 HL128964, U01 HL137880, P01 HL114501, R01 HL122438, R01 HL136682 (F.J.M.) and T32-HL134629 and a research grant from the Stony Wold-Herbert Fund (W.Z.Z). SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C), grants from the NIH/NHLBI (U01 HL137880 and U24 HL141762), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan. Funding Information: The authors thank the SPIROMICS participants and participating physicians, investigators and staff for making this research possible. More information about the study and how to access SPIROMICS data is available at www.spiromics.org. The authors would like to acknowledge the University of North Carolina at Chapel Hill BioSpecimen Processing Facility for sample processing, storage, and sample disbursements (http://bsp.web.unc.edu/). We would like to acknowledge the following current and former investigators of the SPIROMICS sites and reading centers: Neil E. Alexis, MD; Wayne H. Anderson, PhD; Mehrdad Arjomandi, MD; Igor Barjaktarevic, MD, PhD; R. Graham Barr, MD, DrPH; Patricia Basta, PhD; Lori A. Bateman, MSc; Surya P. Bhatt, MD; Eugene R. Bleecker, MD; Richard C. Boucher, MD; Russell P. Bowler, MD, PhD; Stephanie A. Christenson, MD; Alejandro P. Comellas, MD; Christopher B. Cooper, MD, PhD; David J. Couper, PhD; Gerard J. Criner, MD; Ronald G. Crystal, MD; Jeffrey L. Curtis, MD; Claire M. Doerschuk, MD; Mark T. Dransfield, MD; Brad Drummond, MD; Christine M. Freeman, PhD; Craig Galban, PhD; MeiLan K. Han, MD, MS; Nadia N. Hansel, MD, MPH; Annette T. Hastie, PhD; Eric A. Hoffman, PhD; Yvonne Huang, MD; Robert J. Kaner, MD; Richard E. Kanner, MD; Eric C. Kleerup, MD; Jerry A. Krishnan, MD, PhD; Lisa M. LaVange, PhD; Stephen C. Lazarus, MD; Fernando J. Martinez, MD, MS; Deborah A. Meyers, PhD; Wendy C. Moore, MD; John D. Newell Jr, MD; Robert Paine III, MD; Laura Paulin, MD, MHS; Stephen P. Peters, MD, PhD; Cheryl Pirozzi, MD; Nirupama Putcha, MD, MHS; Elizabeth C. Oelsner, MD, MPH; Wanda K. O?Neal, PhD; Victor E. Ortega, MD, PhD; Sanjeev Raman, MBBS, MD; Stephen I. Rennard, MD; Donald P. Tashkin, MD; J. Michael Wells, MD; Robert A. Wise, MD; and Prescott G. Woodruff, MD, MPH. The project officers from the Lung Division of the National Heart, Lung, and Blood Institute were Lisa Postow, PhD, and Lisa Viviano, BSN. Publisher Copyright: © 2021, The Author(s).
PY - 2021/4/26
Y1 - 2021/4/26
N2 - 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
AB - 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
KW - COPD
KW - Mitochondrial dysfunction
KW - SPIROMICS
KW - mtDNA
UR - http://www.scopus.com/inward/record.url?scp=85104874615&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104874615&partnerID=8YFLogxK
U2 - 10.1186/s12931-021-01707-x
DO - 10.1186/s12931-021-01707-x
M3 - Article
C2 - 33902556
AN - SCOPUS:85104874615
VL - 22
JO - Respiratory Research
JF - Respiratory Research
SN - 1465-9921
IS - 1
M1 - 126
ER -