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Association of urine mitochondrial DNA with clinical measures of COPD in the SPIROMICS cohort.

TitleAssociation of urine mitochondrial DNA with clinical measures of COPD in the SPIROMICS cohort.
Publication TypeJournal Article
Year of Publication2020
AuthorsZhang WZ, Rice MC, Hoffman KL, Oromendia C, Barjaktarevic IZ, J Wells M, Hastie AT, Labaki WW, Cooper CB, Comellas AP, Criner GJ, Krishnan JA, Paine R, Hansel NN, Bowler RP, R Barr G, Peters SP, Woodruff PG, Curtis JL, Han MK, Ballman KV, Martinez FJ, Choi AMk, Nakahira K, Cloonan SM, Choi ME
Corporate AuthorsSPIROMICS Investigators
JournalJCI Insight
Volume5
Issue3
Date Published2020 Feb 13
ISSN2379-3708
Abstract

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.

DOI10.1172/jci.insight.133984
Alternate JournalJCI Insight
PubMed ID31895696
PubMed Central IDPMC7098791
Grant ListU24 HL141762 / HL / NHLBI NIH HHS / United States
R00 HL125899 / HL / NHLBI NIH HHS / United States
R01 HL133801 / HL / NHLBI NIH HHS / United States
K24 HL137013 / HL / NHLBI NIH HHS / United States
HHSN268200900015C / HL / NHLBI NIH HHS / United States
HHSN268200900016C / HL / NHLBI NIH HHS / United States
U01 HL137880 / HL / NHLBI NIH HHS / United States
R01 HL122438 / HL / NHLBI NIH HHS / United States
R01 HL132198 / HL / NHLBI NIH HHS / United States
HHSN268200900018C / HL / NHLBI NIH HHS / United States
HHSN268200900013C / HL / NHLBI NIH HHS / United States
R01 HL136682 / HL / NHLBI NIH HHS / United States
T32 HL134629 / HL / NHLBI NIH HHS / United States
HHSN268200900014C / HL / NHLBI NIH HHS / United States
U01 HL128964 / HL / NHLBI NIH HHS / United States
HHSN268200900019C / HL / NHLBI NIH HHS / United States
KL2 TR002385 / TR / NCATS NIH HHS / United States
HHSN268200900017C / HL / NHLBI NIH HHS / United States
HHSN268200900020C / HL / NHLBI NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States
P01 HL114501 / HL / NHLBI NIH HHS / United States
Division: 
Biostatistics
Category: 
Faculty Publication