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

• Published in: Journal of allergy and clinical immunology 2024-09
• Main Authors: Xu, Weiling, Hong, Yun Soo, Hu, Bo, Comhair, Suzy A.A., Janocha, Allison J., Zein, Joe G., Chen, Ruoying, Meyers, Deborah A., Mauger, David T., Ortega, Victor E., Bleecker, Eugene R., Castro, Mario, Denlinger, Loren C., Fahy, John V., Israel, Elliot, Levy, Bruce D., Jarjour, Nizar N., Moore, Wendy C., Wenzel, Sally E., Gaston, Benjamin, Liu, Chunyu, Arking, Dan E., Erzurum, Serpil C.
• Format: Article
• Language: English
• Subjects: asthma; exacerbations; Mitochondrial DNA
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2024.08.022

[Display omitted] 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. We investigated whether lower levels of mtDNA-CN are associated with asthma diagnosis, severity, and exacerbations. 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). 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. 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.