线粒体DNA拷贝数变异与哮喘风险、严重程度和急性发作的相关性分析
2024/10/29
摘要
背景：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）已被用作反映线粒体功能的指标，在心血管疾病和癌症人群的研究中，mtDNA-CN水平较低表明线粒体功能障碍。
目的：本研究旨在探索较低水平的mtDNA-CN是否与哮喘诊断、严重程度和急性发作有关。
方法：在两个队列患者的血样本中评估mtDNA-CN：英国生物库（UKB）（哮喘，n=39147；无哮喘，n=302302）和严重哮喘研究计划（SARP）（哮喘，n=1283；非严重哮喘，n=703）。
结果：在UKB中，哮喘患者的mtDNA-CN低于非哮喘患者（β，-0.006，[95%置信区间，-0.008至-0.003]，P= 6.23×10-6）。在UKB和SARP队列中，较低的mtDNA-CN与哮喘患病率有关，但与严重程度无关。mtDNA-CN随年龄增长而下降，但在所有年龄段，哮喘患者的mtDNA-CN均低于非哮喘患者。在为期一年的SARP纵向研究中，mtDNA-CN与急性加重风险相关；mtDNA-CN最高的患者发生急性加重的风险最低（比值比0.333，[95%置信区间，0.173至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。孟德尔随机化研究表明，哮喘相关遗传变异与mtDNA-CN之间存在潜在因果关系。
结论：哮喘患者的mtDNA-CN低于非哮喘患者，并与哮喘急性加重相关。哮喘中的低mtDNA-CN并非通过炎症介导，而与哮喘的遗传易感性相关。
Mitochondrial DNA copy number variation in asthma risk, severity, and exacerbations.
Jabeen MF, Sanderson ND, Tinè M, Donachie G, Barber C, Azim A, Lau LCK, Brown T, Pavord ID, Chauhan A, Klenerman P, Street TL, Marchi E, Howarth PH, Hinks TSC.
Xu W, Hong YS, Hu B, Comhair SAA, Janocha AJ, Zein JG, Chen R, Meyers DA, Mauger DT, Ortega VE, Bleecker ER, Castro M, Denlinger LC, Fahy JV, Israel E, Levy BD, Jarjour NN, Moore WC, Wenzel SE, Gaston B, Liu C, Arking DE, Erzurum SC; National Heart, Lung, and Blood Institute (NHLBI) Severe Asthma Research Program and TOPMed mtDNA Working Group in NHLBI Transomics for Precision Medicine (TOPMed) Consortium.
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.
背景：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）已被用作反映线粒体功能的指标，在心血管疾病和癌症人群的研究中，mtDNA-CN水平较低表明线粒体功能障碍。
目的：本研究旨在探索较低水平的mtDNA-CN是否与哮喘诊断、严重程度和急性发作有关。
方法：在两个队列患者的血样本中评估mtDNA-CN：英国生物库（UKB）（哮喘，n=39147；无哮喘，n=302302）和严重哮喘研究计划（SARP）（哮喘，n=1283；非严重哮喘，n=703）。
结果：在UKB中，哮喘患者的mtDNA-CN低于非哮喘患者（β，-0.006，[95%置信区间，-0.008至-0.003]，P= 6.23×10-6）。在UKB和SARP队列中，较低的mtDNA-CN与哮喘患病率有关，但与严重程度无关。mtDNA-CN随年龄增长而下降，但在所有年龄段，哮喘患者的mtDNA-CN均低于非哮喘患者。在为期一年的SARP纵向研究中，mtDNA-CN与急性加重风险相关；mtDNA-CN最高的患者发生急性加重的风险最低（比值比0.333，[95%置信区间，0.173至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。孟德尔随机化研究表明，哮喘相关遗传变异与mtDNA-CN之间存在潜在因果关系。
结论：哮喘患者的mtDNA-CN低于非哮喘患者，并与哮喘急性加重相关。哮喘中的低mtDNA-CN并非通过炎症介导，而与哮喘的遗传易感性相关。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2024 Sep 3:S0091-6749(24)00906-0. doi: 10.1016/j.jaci.2024.08.022.)
(J Allergy Clin Immunol. 2024 Sep 3:S0091-6749(24)00906-0. doi: 10.1016/j.jaci.2024.08.022.)
Mitochondrial DNA copy number variation in asthma risk, severity, and exacerbations.
Jabeen MF, Sanderson ND, Tinè M, Donachie G, Barber C, Azim A, Lau LCK, Brown T, Pavord ID, Chauhan A, Klenerman P, Street TL, Marchi E, Howarth PH, Hinks TSC.
Xu W, Hong YS, Hu B, Comhair SAA, Janocha AJ, Zein JG, Chen R, Meyers DA, Mauger DT, Ortega VE, Bleecker ER, Castro M, Denlinger LC, Fahy JV, Israel E, Levy BD, Jarjour NN, Moore WC, Wenzel SE, Gaston B, Liu C, Arking DE, Erzurum SC; National Heart, Lung, and Blood Institute (NHLBI) Severe Asthma Research Program and TOPMed mtDNA Working Group in NHLBI Transomics for Precision Medicine (TOPMed) Consortium.
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.
