Mitochondrial DNA Copy Number Variation in Asthma Risk, Severity, and Exacerbations
Rationale: Although airway oxidative stress and inflammation are central to asthma pathogenesis, there is limited knowledge of the relationship of asthma risk, severity, or exacerbations to mitochondrial dysfunction, which is pivotal to oxidant generation and inflammation.
Objectives: We investigated whether mitochondrial DNA copy number (mtDNA-CN) as a measure of mitochondrial function is associated with asthma diagnosis, severity, oxidative stress, and exacerbations.
Methods: We measured mtDNA-CN in blood in two cohorts. In the UK Biobank (UKB), we compared mtDNA-CN in mild and moderate-severe asthmatics to non-asthmatics. In the Severe Asthma Research Program (SARP), we evaluated mtDNA-CN in relation to asthma severity, biomarkers of oxidative stress and inflammation, and exacerbations.
Measures and Main Results: In UK Biobank, asthmatics (n = 29,768) have lower mtDNA-CN compared to non-asthmatics (n = 239,158) (beta, -0.026 [95% CI, -0.038 to -0.014], P = 2.46×10-5). While lower mtDNA-CN is associated with asthma, mtDNA-CN did not differ by asthma severity in either UKB or SARP. Biomarkers of inflammation show that asthmatics have higher white blood cells (WBC), neutrophils, eosinophils, fraction exhaled nitric oxide (FENO), and lower superoxide dismutase (SOD) than non-asthmatics, confirming greater oxidative stress in asthma. In one year follow-up in SARP, higher mtDNA-CN is associated with reduced risk of three or more exacerbations in the subsequent year (OR 0.352 [95% CI, 0.164 to 0.753], P = 0.007).
Conclusions: Asthma is characterized by mitochondrial dysfunction. Higher mtDNA-CN identifies an exacerbation-resistant asthma phenotype, suggesting mitochondrial function is important in exacerbation risk.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2023 |
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| Enthalten in: |
medRxiv : the preprint server for health sciences - (2023) vom: 05. Dez. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Xu, Weiling [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 25.12.2023 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2023.12.05.23299392 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM365967998 |
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| 100 | 1 | |a Xu, Weiling |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Mitochondrial DNA Copy Number Variation in Asthma Risk, Severity, and Exacerbations |
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| 500 | |a Date Revised 25.12.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Rationale: Although airway oxidative stress and inflammation are central to asthma pathogenesis, there is limited knowledge of the relationship of asthma risk, severity, or exacerbations to mitochondrial dysfunction, which is pivotal to oxidant generation and inflammation | ||
| 520 | |a Objectives: We investigated whether mitochondrial DNA copy number (mtDNA-CN) as a measure of mitochondrial function is associated with asthma diagnosis, severity, oxidative stress, and exacerbations | ||
| 520 | |a Methods: We measured mtDNA-CN in blood in two cohorts. In the UK Biobank (UKB), we compared mtDNA-CN in mild and moderate-severe asthmatics to non-asthmatics. In the Severe Asthma Research Program (SARP), we evaluated mtDNA-CN in relation to asthma severity, biomarkers of oxidative stress and inflammation, and exacerbations | ||
| 520 | |a Measures and Main Results: In UK Biobank, asthmatics (n = 29,768) have lower mtDNA-CN compared to non-asthmatics (n = 239,158) (beta, -0.026 [95% CI, -0.038 to -0.014], P = 2.46×10-5). While lower mtDNA-CN is associated with asthma, mtDNA-CN did not differ by asthma severity in either UKB or SARP. Biomarkers of inflammation show that asthmatics have higher white blood cells (WBC), neutrophils, eosinophils, fraction exhaled nitric oxide (FENO), and lower superoxide dismutase (SOD) than non-asthmatics, confirming greater oxidative stress in asthma. In one year follow-up in SARP, higher mtDNA-CN is associated with reduced risk of three or more exacerbations in the subsequent year (OR 0.352 [95% CI, 0.164 to 0.753], P = 0.007) | ||
| 520 | |a Conclusions: Asthma is characterized by mitochondrial dysfunction. Higher mtDNA-CN identifies an exacerbation-resistant asthma phenotype, suggesting mitochondrial function is important in exacerbation risk | ||
| 650 | 4 | |a Preprint | |
| 650 | 4 | |a Asthma | |
| 650 | 4 | |a Exacerbations | |
| 650 | 4 | |a Mitochondrial DNA | |
| 700 | 1 | |a Hong, Yun Soo |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Comhair, Suzy A A |e verfasserin |4 aut | |
| 700 | 1 | |a Janocha, Allison J |e verfasserin |4 aut | |
| 700 | 1 | |a Zein, Joe G |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ruoying |e verfasserin |4 aut | |
| 700 | 1 | |a Meyers, Deborah A |e verfasserin |4 aut | |
| 700 | 1 | |a Mauger, David T |e verfasserin |4 aut | |
| 700 | 1 | |a Ortega, Victor E |e verfasserin |4 aut | |
| 700 | 1 | |a Bleecker, Eugene R |e verfasserin |4 aut | |
| 700 | 1 | |a Castro, Mario |e verfasserin |4 aut | |
| 700 | 1 | |a Denlinger, Loren C |e verfasserin |4 aut | |
| 700 | 1 | |a Fahy, John V |e verfasserin |4 aut | |
| 700 | 1 | |a Israel, Elliot |e verfasserin |4 aut | |
| 700 | 1 | |a Levy, Bruce D |e verfasserin |4 aut | |
| 700 | 1 | |a Jarjour, Nizar N |e verfasserin |4 aut | |
| 700 | 1 | |a Moore, Wendy C |e verfasserin |4 aut | |
| 700 | 1 | |a Wenzel, Sally E |e verfasserin |4 aut | |
| 700 | 1 | |a Gaston, Benjamin |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Chunyu |e verfasserin |4 aut | |
| 700 | 1 | |a Arking, Dan E |e verfasserin |4 aut | |
| 700 | 1 | |a Erzurum, Serpil C |e verfasserin |4 aut | |
| 700 | 0 | |a National Heart, Lung, and Blood Institute (NHLBI) Severe Asthma Research Program (SARP) and TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium |e verfasserin |4 aut | |
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