Asthma and its relationship to mitochondrial copy number: Results from the Asthma Translational Genomics Collaborative (ATGC) of the Trans-Omics for Precision Medicine (TOPMed) program.
Adult
Black or African American
/ genetics
Asthma
/ ethnology
Base Sequence
Cohort Studies
DNA Copy Number Variations
DNA, Mitochondrial
/ blood
Electron Transport Chain Complex Proteins
/ genetics
Female
Flow Cytometry
Humans
Leukocytes
/ ultrastructure
Logistic Models
Male
Middle Aged
Proportional Hazards Models
RNA
/ genetics
Sensitivity and Specificity
Translational Research, Biomedical
Whole Genome Sequencing
Young Adult
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
05
05
2020
accepted:
30
10
2020
entrez:
25
11
2020
pubmed:
26
11
2020
medline:
5
1
2021
Statut:
epublish
Résumé
Mitochondria support critical cellular functions, such as energy production through oxidative phosphorylation, regulation of reactive oxygen species, apoptosis, and calcium homeostasis. Given the heightened level of cellular activity in patients with asthma, we sought to determine whether mitochondrial DNA (mtDNA) copy number measured in peripheral blood differed between individuals with and without asthma. Whole genome sequence data was generated as part of the Trans-Omics for Precision Medicine (TOPMed) Program on participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) and the Study of African Americans, Asthma, Genes, & Environment II (SAGE II). We restricted our analysis to individuals who self-identified as African American (3,651 asthma cases and 1,344 controls). Mitochondrial copy number was estimated using the sequencing read depth ratio for the mitochondrial and nuclear genomes. Respiratory complex expression was assessed using RNA-sequencing. Average mitochondrial copy number was significantly higher among individuals with asthma when compared with controls (SAPPHIRE: 218.60 vs. 200.47, P<0.001; SAGE II: 235.99 vs. 223.07, P<0.001). Asthma status was significantly associated with mitochondrial copy number after accounting for potential explanatory variables, such as participant age, sex, leukocyte counts, and mitochondrial haplogroup. Despite the consistent relationship between asthma status and mitochondrial copy number, the latter was not associated with time-to-exacerbation or patient-reported asthma control. Mitochondrial respiratory complex gene expression was disproportionately lower in individuals with asthma when compared with individuals without asthma and other protein-encoding genes. We observed a robust association between asthma and higher mitochondrial copy number. Asthma having an effect on mitochondria function was also supported by lower respiratory complex gene expression in this group.
Sections du résumé
BACKGROUND
Mitochondria support critical cellular functions, such as energy production through oxidative phosphorylation, regulation of reactive oxygen species, apoptosis, and calcium homeostasis.
OBJECTIVE
Given the heightened level of cellular activity in patients with asthma, we sought to determine whether mitochondrial DNA (mtDNA) copy number measured in peripheral blood differed between individuals with and without asthma.
METHODS
Whole genome sequence data was generated as part of the Trans-Omics for Precision Medicine (TOPMed) Program on participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) and the Study of African Americans, Asthma, Genes, & Environment II (SAGE II). We restricted our analysis to individuals who self-identified as African American (3,651 asthma cases and 1,344 controls). Mitochondrial copy number was estimated using the sequencing read depth ratio for the mitochondrial and nuclear genomes. Respiratory complex expression was assessed using RNA-sequencing.
RESULTS
Average mitochondrial copy number was significantly higher among individuals with asthma when compared with controls (SAPPHIRE: 218.60 vs. 200.47, P<0.001; SAGE II: 235.99 vs. 223.07, P<0.001). Asthma status was significantly associated with mitochondrial copy number after accounting for potential explanatory variables, such as participant age, sex, leukocyte counts, and mitochondrial haplogroup. Despite the consistent relationship between asthma status and mitochondrial copy number, the latter was not associated with time-to-exacerbation or patient-reported asthma control. Mitochondrial respiratory complex gene expression was disproportionately lower in individuals with asthma when compared with individuals without asthma and other protein-encoding genes.
CONCLUSIONS
We observed a robust association between asthma and higher mitochondrial copy number. Asthma having an effect on mitochondria function was also supported by lower respiratory complex gene expression in this group.
Identifiants
pubmed: 33237978
doi: 10.1371/journal.pone.0242364
pii: PONE-D-20-13242
pmc: PMC7688161
doi:
Substances chimiques
DNA, Mitochondrial
0
Electron Transport Chain Complex Proteins
0
RNA
63231-63-0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0242364Subventions
Organisme : NHLBI NIH HHS
ID : R35 HL145235
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI077439
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL117004
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL117626
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL120393
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI079139
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI061774
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL117004
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL079055
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL118267
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141845
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK064695
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK113003
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES015794
Pays : United States
Organisme : NIEHS NIH HHS
ID : R21 ES024844
Pays : United States
Organisme : NIMHD NIH HHS
ID : P60 MD006902
Pays : United States
Organisme : NIMHD NIH HHS
ID : R01 MD010443
Pays : United States
Déclaration de conflit d'intérêts
Dr. Abecasis reported receiving personal fees and salary support from Regeneron Pharmaceuticals. This support was outside of the submitted work and did not alter our adherence to PLOS ONE policies regarding the sharing of data and/or research materials. The remaining authors reported no competing interests.
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