PMID- 31895696
OWN - NLM
STAT- MEDLINE
DCOM- 20210621
LR  - 20210621
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 5
IP  - 3
DP  - 2020 Feb 13
TI  - Association of urine mitochondrial DNA with clinical measures of COPD in the 
      SPIROMICS cohort.
LID - 133984 [pii]
LID - 10.1172/jci.insight.133984 [doi]
LID - e133984
AB  - BACKGROUNDMitochondrial dysfunction, a proposed mechanism of chronic obstructive 
      pulmonary disease (COPD) pathogenesis, is associated with the leakage of 
      mitochondrial DNA (mtDNA), which may be detected extracellularly in various 
      bodily fluids. Despite evidence for the increased prevalence of chronic kidney 
      disease in COPD subjects and for mitochondrial dysfunction in the kidneys of 
      murine COPD models, whether urine mtDNA (u-mtDNA) associates with measures of 
      disease severity in COPD is unknown.METHODSCell-free u-mtDNA, defined as copy 
      number of mitochondrially encoded NADH dehydrogenase-1 (MTND1) gene, was measured 
      by quantitative PCR and normalized to urine creatinine in cell-free urine samples 
      from participants in the Subpopulations and Intermediate Outcome Measures in COPD 
      Study (SPIROMICS) cohort. Urine albumin/creatinine ratios (UACR) were measured in 
      the same samples. Associations between u-mtDNA, UACR, and clinical disease 
      parameters - including FEV1 % predicted, clinical measures of exercise tolerance, 
      respiratory symptom burden, and chest CT measures of lung structure - were 
      examined.RESULTSU-mtDNA and UACR levels were measured in never smokers (n = 64), 
      smokers without airflow obstruction (n = 109), participants with mild/moderate 
      COPD (n = 142), and participants with severe COPD (n = 168). U-mtDNA was 
      associated with increased respiratory symptom burden, especially among smokers 
      without COPD. Significant sex differences in u-mtDNA levels were observed, with 
      females having higher u-mtDNA levels across all study subgroups. U-mtDNA 
      associated with worse spirometry and CT emphysema in males only and with worse 
      respiratory symptoms in females only. Similar associations were not found with 
      UACR.CONCLUSIONU-mtDNA levels may help to identify distinct clinical phenotypes 
      and underlying pathobiological differences in males versus females with 
      COPD.TRIAL REGISTRATIONThis study has been registered at ClinicalTrials.gov ( 
      NCT01969344).FUNDINGUS NIH, National Heart, Lung and Blood Institute, 
      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.
FAU - Zhang, William Z
AU  - Zhang WZ
AD  - Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill 
      Department of Medicine, New York, New York, USA.
AD  - New York-Presbyterian Hospital, Weill Cornell Medicine, New York, New York, USA.
FAU - Rice, Michelle C
AU  - Rice MC
AD  - Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of 
      Medicine, and.
FAU - Hoffman, Katherine L
AU  - Hoffman KL
AD  - Department of Healthcare Policy and Research, Division of Biostatistics and 
      Epidemiology, Weill Cornell Medicine, New York, New York, USA.
FAU - Oromendia, Clara
AU  - Oromendia C
AD  - Department of Healthcare Policy and Research, Division of Biostatistics and 
      Epidemiology, Weill Cornell Medicine, New York, New York, USA.
FAU - Barjaktarevic, Igor Z
AU  - Barjaktarevic IZ
AD  - Division of Pulmonary and Critical Care Medicine, UCLA Medical Center, Los 
      Angeles, California, USA.
FAU - Wells, J Michael
AU  - Wells JM
AD  - University of Alabama at Birmingham, Birmingham, Alabama, USA.
FAU - Hastie, Annette T
AU  - Hastie AT
AD  - Pulmonary, Critical Care, Allergy, and Immunologic Medicine, Wake Forest School 
      of Medicine, Winston-Salem, North Carolina, USA.
FAU - Labaki, Wassim W
AU  - Labaki WW
AD  - Division of Pulmonary and Critical Care Medicine, University of Michigan Health 
      System, Ann Arbor, Michigan, USA.
FAU - Cooper, Christopher B
AU  - Cooper CB
AD  - Division of Pulmonary and Critical Care Medicine, UCLA Medical Center, Los 
      Angeles, California, USA.
FAU - Comellas, Alejandro P
AU  - Comellas AP
AD  - Division of Pulmonary and Critical Care, University of Iowa, Iowa City, Iowa, 
      USA.
FAU - Criner, Gerard J
AU  - Criner GJ
AD  - Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at 
      Temple University, Philadelphia, Pennsylvania, USA.
FAU - Krishnan, Jerry A
AU  - Krishnan JA
AD  - Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois 
      College of Medicine, Chicago, Illinois, USA.
FAU - Paine, Robert 3rd
AU  - Paine R 3rd
AD  - Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, 
      University of Utah, Salt Lake City, Utah, USA.
FAU - Hansel, Nadia N
AU  - Hansel NN
AD  - Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School 
      of Medicine, Baltimore, Maryland, USA.
FAU - Bowler, Russell P
AU  - Bowler RP
AD  - Division of Pulmonary, Critical Care Medicine, National Jewish Health, Denver, 
      Colorado, USA.
FAU - Barr, R Graham
AU  - Barr RG
AD  - Columbia University Medical Center, New York, New York, USA.
FAU - Peters, Stephen P
AU  - Peters SP
AD  - Pulmonary, Critical Care, Allergy, and Immunologic Medicine, Wake Forest School 
      of Medicine, Winston-Salem, North Carolina, USA.
FAU - Woodruff, Prescott G
AU  - Woodruff PG
AD  - Division of Pulmonary and Critical Care Medicine, UCSF, School of Medicine, San 
      Francisco, California, USA.
FAU - Curtis, Jeffrey L
AU  - Curtis JL
AD  - Division of Pulmonary and Critical Care Medicine, University of Michigan Health 
      System, Ann Arbor, Michigan, USA.
AD  - Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA.
FAU - Han, Meilan K
AU  - Han MK
AD  - Division of Pulmonary and Critical Care Medicine, University of Michigan Health 
      System, Ann Arbor, Michigan, USA.
FAU - Ballman, Karla V
AU  - Ballman KV
AD  - Department of Healthcare Policy and Research, Division of Biostatistics and 
      Epidemiology, Weill Cornell Medicine, New York, New York, USA.
FAU - Martinez, Fernando J
AU  - Martinez FJ
AD  - Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill 
      Department of Medicine, New York, New York, USA.
AD  - New York-Presbyterian Hospital, Weill Cornell Medicine, New York, New York, USA.
FAU - Choi, Augustine Mk
AU  - Choi AM
AD  - Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill 
      Department of Medicine, New York, New York, USA.
AD  - New York-Presbyterian Hospital, Weill Cornell Medicine, New York, New York, USA.
FAU - Nakahira, Kiichi
AU  - Nakahira K
AD  - Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill 
      Department of Medicine, New York, New York, USA.
FAU - Cloonan, Suzanne M
AU  - Cloonan SM
AD  - Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill 
      Department of Medicine, New York, New York, USA.
FAU - Choi, Mary E
AU  - Choi ME
AD  - New York-Presbyterian Hospital, Weill Cornell Medicine, New York, New York, USA.
AD  - Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of 
      Medicine, and.
CN  - SPIROMICS Investigators
LA  - eng
SI  - ClinicalTrials.gov/NCT01969344
GR  - U24 HL141762/HL/NHLBI NIH HHS/United States
GR  - R00 HL125899/HL/NHLBI NIH HHS/United States
GR  - P30 ES005605/ES/NIEHS NIH HHS/United States
GR  - R01 HL133801/HL/NHLBI NIH HHS/United States
GR  - K24 HL137013/HL/NHLBI NIH HHS/United States
GR  - HHSN268200900015C/HL/NHLBI NIH HHS/United States
GR  - I01 CX000911/CX/CSRD VA/United States
GR  - U01 HL137880/HL/NHLBI NIH HHS/United States
GR  - R01 HL122438/HL/NHLBI NIH HHS/United States
GR  - R01 HL132198/HL/NHLBI NIH HHS/United States
GR  - HHSN268200900018C/HL/NHLBI NIH HHS/United States
GR  - HHSN268200900013C/HL/NHLBI NIH HHS/United States
GR  - R01 HL136682/HL/NHLBI NIH HHS/United States
GR  - T32 HL134629/HL/NHLBI NIH HHS/United States
GR  - HHSN268200900014C/HL/NHLBI NIH HHS/United States
GR  - U01 HL128964/HL/NHLBI NIH HHS/United States
GR  - HHSN268200900019C/HL/NHLBI NIH HHS/United States
GR  - HHSN268200900016C/HL/NHLBI NIH HHS/United States
GR  - K08 HL123940/HL/NHLBI NIH HHS/United States
GR  - KL2 TR002385/TR/NCATS NIH HHS/United States
GR  - HHSN268200900017C/HL/NHLBI NIH HHS/United States
GR  - HHSN268200900020C/HL/NHLBI NIH HHS/United States
GR  - UL1 TR000457/TR/NCATS NIH HHS/United States
GR  - P01 HL114501/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200213
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
RN  - 0 (Biomarkers)
RN  - 0 (DNA, Mitochondrial)
SB  - IM
MH  - Aged
MH  - Biomarkers/urine
MH  - Cohort Studies
MH  - DNA, Mitochondrial/*urine
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Pulmonary Disease, Chronic Obstructive/physiopathology/*urine
PMC - PMC7098791
OTO - NOTNLM
OT  - COPD
OT  - Mitochondria
OT  - Nephrology
OT  - Pulmonology
COIS- Conflict of interest: See supplemental material for conflict of interest 
      statement.
EDAT- 2020/01/03 06:00
MHDA- 2021/06/22 06:00
PMCR- 2020/02/13
CRDT- 2020/01/03 06:00
PHST- 2019/10/02 00:00 [received]
PHST- 2019/12/26 00:00 [accepted]
PHST- 2020/01/03 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/01/03 06:00 [entrez]
PHST- 2020/02/13 00:00 [pmc-release]
AID - 133984 [pii]
AID - 10.1172/jci.insight.133984 [doi]
PST - epublish
SO  - JCI Insight. 2020 Feb 13;5(3):e133984. doi: 10.1172/jci.insight.133984.