Weiling Xu, Yun Soo Hong, Bo Hu, Suzy A A Comhair, Allison J Janocha, Joe G Zein, Ruoying Chen, Deborah A Meyers, David T Mauger, Victor E Ortega, Eugene R Bleecker, Mario Castro, Loren C Denlinger, John V Fahy, Elliot Israel, Bruce D Levy, Nizar N Jarjour, Wendy C Moore, Sally E Wenzel, Benjamin Gaston, Chunyu Liu, Dan E Arking, Serpil C Erzurum
{"title":"线粒体 DNA 拷贝数变异与哮喘风险、严重程度和恶化的关系。","authors":"Weiling Xu, Yun Soo Hong, Bo Hu, Suzy A A Comhair, Allison J Janocha, Joe G Zein, Ruoying Chen, Deborah A Meyers, David T Mauger, Victor E Ortega, Eugene R Bleecker, Mario Castro, Loren C Denlinger, John V Fahy, Elliot Israel, Bruce D Levy, Nizar N Jarjour, Wendy C Moore, Sally E Wenzel, Benjamin Gaston, Chunyu Liu, Dan E Arking, Serpil C Erzurum","doi":"10.1016/j.jaci.2024.08.022","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objectives: </strong>We investigate whether lower levels of mtDNA-CN are associated with asthma diagnosis, severity, and exacerbations.</p><p><strong>Methods: </strong>MtDNA-CN is evaluated in blood from two cohorts: UK Biobank (UKB) (asthmatics n = 39,147; non-asthmatics n = 302,302) and Severe Asthma Research Program (SARP) (n = 1283 asthmatics, non-severe n = 703).</p><p><strong>Results: </strong>Asthmatics have lower mtDNA-CN compared to non-asthmatics in UKB (beta, -0.006 [95% CI, -0.008 to -0.003], P = 6.23×10<sup>-6</sup>). Lower mtDNA-CN is associated with asthma prevalence, but not severity in UKB or SARP. mtDNA-CN declines with age but is lower in asthma than in non-asthmatics at all ages. In one-year longitudinal study in SARP, mtDNA-CN is associated with risk of exacerbation; those with highest mtDNA-CN have the lowest risk of exacerbation [OR 0.333 [95% CI, 0.173 to 0.542], P = 0.001]. Biomarkers of inflammation and oxidative stress are higher in asthma than non-asthmatics, but the lower mtDNA-CN in asthma are independent of general inflammation or oxidative stress. Mendelian Randomization (MR) studies suggest a potential causal relationship between asthma-associated genetic variants and mtDNA-CN.</p><p><strong>Conclusion: </strong>MtDNA-CN are lower in asthmatics than in non-asthmatics and are associated with exacerbations. Low mtDNA-CN in asthma are not mediated through inflammation but are associated with the genetic predisposition to asthma.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4000,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mitochondrial DNA Copy Number Variation in Asthma Risk, Severity, and Exacerbations.\",\"authors\":\"Weiling Xu, Yun Soo Hong, Bo Hu, Suzy A A Comhair, Allison J Janocha, Joe G Zein, Ruoying Chen, Deborah A Meyers, David T Mauger, Victor E Ortega, Eugene R Bleecker, Mario Castro, Loren C Denlinger, John V Fahy, Elliot Israel, Bruce D Levy, Nizar N Jarjour, Wendy C Moore, Sally E Wenzel, Benjamin Gaston, Chunyu Liu, Dan E Arking, Serpil C Erzurum\",\"doi\":\"10.1016/j.jaci.2024.08.022\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Objectives: </strong>We investigate whether lower levels of mtDNA-CN are associated with asthma diagnosis, severity, and exacerbations.</p><p><strong>Methods: </strong>MtDNA-CN is evaluated in blood from two cohorts: UK Biobank (UKB) (asthmatics n = 39,147; non-asthmatics n = 302,302) and Severe Asthma Research Program (SARP) (n = 1283 asthmatics, non-severe n = 703).</p><p><strong>Results: </strong>Asthmatics have lower mtDNA-CN compared to non-asthmatics in UKB (beta, -0.006 [95% CI, -0.008 to -0.003], P = 6.23×10<sup>-6</sup>). Lower mtDNA-CN is associated with asthma prevalence, but not severity in UKB or SARP. mtDNA-CN declines with age but is lower in asthma than in non-asthmatics at all ages. In one-year longitudinal study in SARP, mtDNA-CN is associated with risk of exacerbation; those with highest mtDNA-CN have the lowest risk of exacerbation [OR 0.333 [95% CI, 0.173 to 0.542], P = 0.001]. Biomarkers of inflammation and oxidative stress are higher in asthma than non-asthmatics, but the lower mtDNA-CN in asthma are independent of general inflammation or oxidative stress. Mendelian Randomization (MR) studies suggest a potential causal relationship between asthma-associated genetic variants and mtDNA-CN.</p><p><strong>Conclusion: </strong>MtDNA-CN are lower in asthmatics than in non-asthmatics and are associated with exacerbations. Low mtDNA-CN in asthma are not mediated through inflammation but are associated with the genetic predisposition to asthma.</p>\",\"PeriodicalId\":14936,\"journal\":{\"name\":\"Journal of Allergy and Clinical Immunology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":11.4000,\"publicationDate\":\"2024-09-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Allergy and Clinical Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jaci.2024.08.022\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ALLERGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Allergy and Clinical Immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jaci.2024.08.022","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ALLERGY","Score":null,"Total":0}
引用次数: 0
摘要
背景:哮喘的病理生理学与线粒体功能障碍有关:哮喘的病理生理学与线粒体功能障碍有关。线粒体 DNA 拷贝数(mtDNA-CN)被用作线粒体功能的代表,在心血管疾病和癌症的人群研究中,较低的拷贝数表明线粒体功能障碍:我们研究了较低水平的 mtDNA-CN 是否与哮喘诊断、严重程度和恶化有关:方法:在两个队列的血液中对 mtDNA-CN 进行评估:英国生物库(UKB)(哮喘患者 n = 39,147 人;非哮喘患者 n = 302,302 人)和严重哮喘研究计划(SARP)(哮喘患者 n = 1283 人,非严重患者 n = 703 人):在UKB中,与非哮喘患者相比,哮喘患者的mtDNA-CN较低(β值为-0.006 [95% CI, -0.008 to -0.003],P = 6.23×10-6)。mtDNA-CN的降低与哮喘的发病率有关,但与英国哮喘协会或叙利亚哮喘协会的哮喘严重程度无关。mtDNA-CN会随着年龄的增长而降低,但在所有年龄段,哮喘患者的mtDNA-CN都低于非哮喘患者。在对 SARP 进行的为期一年的纵向研究中,mtDNA-CN 与病情恶化的风险有关;mtDNA-CN 最高的人病情恶化的风险最低 [OR 0.333 [95% CI, 0.173 to 0.542], P = 0.001]。哮喘患者的炎症和氧化应激生物标志物高于非哮喘患者,但哮喘患者较低的mtDNA-CN与一般炎症或氧化应激无关。孟德尔随机化(MR)研究表明,哮喘相关基因变异与mtDNA-CN之间可能存在因果关系:结论:哮喘患者的 mtDNA-CN 低于非哮喘患者,且与病情恶化有关。哮喘患者的低 mtDNA-CN 不是通过炎症介导的,而是与哮喘的遗传易感性有关。
Mitochondrial DNA Copy Number Variation in Asthma Risk, Severity, and Exacerbations.
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 investigate whether lower levels of mtDNA-CN are associated with asthma diagnosis, severity, and exacerbations.
Methods: MtDNA-CN is evaluated in blood from two cohorts: UK Biobank (UKB) (asthmatics n = 39,147; non-asthmatics n = 302,302) and Severe Asthma Research Program (SARP) (n = 1283 asthmatics, non-severe n = 703).
Results: Asthmatics have lower mtDNA-CN compared to non-asthmatics in UKB (beta, -0.006 [95% CI, -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 asthma than in non-asthmatics at all ages. In one-year longitudinal study in SARP, mtDNA-CN is associated with risk of exacerbation; those with highest mtDNA-CN have the lowest risk of exacerbation [OR 0.333 [95% CI, 0.173 to 0.542], P = 0.001]. Biomarkers of inflammation and oxidative stress are higher in asthma than non-asthmatics, but the lower mtDNA-CN in asthma are independent of general inflammation or oxidative stress. Mendelian Randomization (MR) studies suggest a potential causal relationship between asthma-associated genetic variants and mtDNA-CN.
Conclusion: MtDNA-CN are lower in asthmatics than in non-asthmatics and are associated with exacerbations. Low mtDNA-CN in asthma are not mediated through inflammation but are associated with the genetic predisposition to asthma.
期刊介绍:
The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.