Feng Qiu, Wei Shao, Xue Qin, Ran Xu, Yifan Liu, Hua Lu
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引用次数: 0
Abstract
Asthma, a chronic respiratory disease affecting millions worldwide, poses a significant public health burden. Cathepsins, a group of proteolytic enzymes, have recently been implicated in asthma pathophysiology, though their exact causal role remains unclear. To address this gap, we conducted univariate and multivariate Mendelian randomization (MR) analyses using data from the INTERVAL study (3301 European ancestry participants) and FinnGen consortium (46,684 asthma cases and 219,734 controls). Our analysis employed inverse variance weighting (IVW), median weighting, and MR-Egger regression to ensure robustness and explore causality from multiple perspectives. Sensitivity analyses were performed to assess heterogeneity and pleiotropy.Results indicated a significant association between elevated cathepsin L2 levels and increased asthma risk (OR 1.058, 95% CI 1.016-1.101, P = 0.006), suggesting a potential role of cathepsin L2 in asthma pathogenesis. No significant effect of asthma status on cathepsin L2 levels was observed (P = 0.550), ruling out reverse causality. Multivariable MR further confirmed the independent association of cathepsin L2 with asthma risk. Sensitivity analyses supported these findings with no evidence of significant pleiotropy.This study is the first to apply Mendelian randomization to explore the causal relationship between cathepsins and asthma, highlighting cathepsin L2 as a key player in asthma pathophysiology. These findings offer novel insights into asthma mechanisms and suggest cathepsin L2 as a potential therapeutic target warranting further investigation.
哮喘是一种影响全世界数百万人的慢性呼吸系统疾病,对公共卫生造成重大负担。组织蛋白酶,一组蛋白水解酶,最近被认为与哮喘病理生理有关,尽管它们的确切因果作用尚不清楚。为了解决这一差距,我们使用INTERVAL研究(3301名欧洲血统参与者)和FinnGen联盟(46,684例哮喘病例和219,734例对照)的数据进行了单变量和多变量孟德尔随机化(MR)分析。我们的分析采用反方差加权(IVW)、中位数加权和MR-Egger回归来确保稳健性,并从多个角度探索因果关系。进行敏感性分析以评估异质性和多效性。结果显示,组织蛋白酶L2水平升高与哮喘风险增加之间存在显著相关性(OR 1.058, 95% CI 1.016-1.101, P = 0.006),提示组织蛋白酶L2在哮喘发病机制中可能发挥作用。哮喘状态对组织蛋白酶L2水平无显著影响(P = 0.550),排除反向因果关系。多变量MR进一步证实了组织蛋白酶L2与哮喘风险的独立关联。敏感性分析支持这些发现,没有明显的多效性证据。本研究首次应用孟德尔随机化方法探索组织蛋白酶与哮喘的因果关系,强调了组织蛋白酶L2在哮喘病理生理中的关键作用。这些发现为哮喘机制提供了新的见解,并表明组织蛋白酶L2作为潜在的治疗靶点值得进一步研究。
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