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. 2025 Apr;155(4):1224-1235.
doi: 10.1016/j.jaci.2024.08.022. Epub 2024 Sep 3.

Mitochondrial DNA copy number variation in asthma risk, severity, and exacerbations

Weiling Xu  1 , Yun Soo Hong  2 , Bo Hu  3 , Suzy A A Comhair  1 , Allison J Janocha  1 , Joe G Zein  4 , Ruoying Chen  3 , Deborah A Meyers  4 , David T Mauger  5 , Victor E Ortega  4 , Eugene R Bleecker  4 , Mario Castro  6 , Loren C Denlinger  7 , John V Fahy  8 , Elliot Israel  9 , Bruce D Levy  9 , Nizar N Jarjour  10 , Wendy C Moore  11 , Sally E Wenzel  12 , Benjamin Gaston  13 , Chunyu Liu  14 , Dan E Arking  2 , Serpil C Erzurum  15 ; National Heart, Lung, and Blood Institute (NHLBI) Severe Asthma Research Program and TOPMed mtDNA Working Group in NHLBI Trans-omics for Precision Medicine (TOPMed) Consortium
Affiliations

Mitochondrial DNA copy number variation in asthma risk, severity, and exacerbations

Weiling Xu et al. J Allergy Clin Immunol. 2025 Apr.

Abstract

Background: Asthma pathophysiology is associated with mitochondrial dysfunction. Mitochondrial DNA copy number (mtDNA-CN) has been used as a proxy of mitochondrial function, with lower levels indicating mitochondrial dysfunction in population studies of cardiovascular diseases and cancers.

Objectives: We investigated whether lower levels of mtDNA-CN are associated with asthma diagnosis, severity, and exacerbations.

Methods: mtDNA-CN is evaluated in blood from 2 cohorts: UK Biobank (UKB) (asthma, n = 39,147; no asthma, n = 302,302) and Severe Asthma Research Program (SARP) (asthma, n = 1283; nonsevere asthma, n = 703).

Results: Individuals with asthma have lower mtDNA-CN compared to individuals without asthma in UKB (beta, -0.006 [95% confidence interval, -0.008 to -0.003], P = 6.23 × 10-6). Lower mtDNA-CN is associated with asthma prevalence, but not severity in UKB or SARP. mtDNA-CN declines with age but is lower in individuals with asthma than in individuals without asthma at all ages. In a 1-year longitudinal study in SARP, mtDNA-CN was associated with risk of exacerbation; those with highest mtDNA-CN had the lowest risk of exacerbation (odds ratio 0.333 [95% confidence interval, 0.173 to 0.542], P = .001). Biomarkers of inflammation and oxidative stress are higher in individuals with asthma than without asthma, but the lower mtDNA-CN in asthma is independent of general inflammation or oxidative stress. Mendelian randomization studies suggest a potential causal relationship between asthma-associated genetic variants and mtDNA-CN.

Conclusion: mtDNA-CN is lower in asthma than in no asthma and is associated with exacerbations. Low mtDNA-CN in asthma is not mediated through inflammation but is associated with a genetic predisposition to asthma.

Keywords: Mitochondrial DNA; asthma; exacerbations.

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Conflict of interest statement

Disclosure statement This research was conducted using the UK Biobank Resource under application 17731. The study was supported by the National Heart, Lung, and Blood Institute (NHLBI; HL081064, HL103453, and HL144569) and the National Center for Advancing Translational Sciences (ULTR000439). The Severe Asthma Research Program (SARP) was supported by awards from the National Heart, Lung, and Blood Institute (U10 HL109172, U10 HL109168, U10 HL109152, U10 HL109257, U10 HL109046, U10 HL109250, U10 HL109164, and U10 HL109086). SARP mitochondrial DNA copy numbers were from the Trans-omics in Precision Medicine (TOPMed) program supported by the NHLBI. Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, was provided by the TOPMed Informatics Research Center (3R01HL117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity quality control, and general program coordination was provided by the TOPMed Data Coordinating Center (R01HL120393; U01HL120393; contract HHSN268201800001I). Industry support was provided for SARP III from AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi-Genzyme-Regeneron, and Teva. The following companies provided financial support for study activities at the Coordinating and Clinical Centers beyond the third year of patient follow-up: AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi-Genzyme-Regeneron, and Teva. These companies had no role in study design or data analysis, and the only restriction on the funds was that they be used to support the SARP initiative. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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