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 = 2.46x10^-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 (F_ENO), 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.

中文翻译：

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线粒体 DNA 拷贝数变异与哮喘风险、严重程度和恶化有关

理由：虽然气道氧化应激和炎症是哮喘发病机制的核心，但对哮喘风险、严重程度或恶化与线粒体功能障碍之间的关系的了解有限，而线粒体功能障碍对于氧化剂的产生和炎症至关重要。目的：我们研究了线粒体 DNA 拷贝数 (mtDNA-CN) 作为线粒体功能的衡量标准是否与哮喘诊断、严重程度、氧化应激和恶化相关。方法：我们测量了两个队列血液中的 mtDNA-CN。在英国生物银行 (UKB)，我们比较了轻度和中重度哮喘患者与非哮喘患者的 mtDNA-CN。在严重哮喘研究计划 (SARP) 中，我们评估了 mtDNA-CN 与哮喘严重程度、氧化应激和炎症生物标志物以及病情加重的关系。措施和主要结果：在英国生物银行中，与非哮喘患者 (n = 239,158) 相比，哮喘患者 (n = 29,768) 的 mtDNA-CN 较低（β，-0.026 [95% CI，-0.038 至 -0.014]，P = 2.46 x10 ^-5 )。虽然较低的 mtDNA-CN 与哮喘相关，但在 UKB 或 SARP 中，mtDNA-CN 并没有因哮喘严重程度而存在差异。炎症生物标志物显示，与非哮喘患者相比，哮喘患者的白细胞 (WBC)、中性粒细胞、嗜酸性粒细胞、呼出一氧化氮 (F _E NO) 分数较高，超氧化物歧化酶 (SOD) 较低，这证实了哮喘患者存在更大的氧化应激。在 SARP 的一年随访中，较高的 mtDNA-CN 与随后一年中三次或多次恶化的风险降低相关（OR 0.352 [95% CI，0.164 至 0.753]，P = 0.007）。结论：哮喘的特点是线粒体功能障碍。较高的 mtDNA-CN 可以识别哮喘的抗恶化表型，表明线粒体功能对于恶化风险很重要。