Causal Role of Immune Cells in Chronic Obstructive Pulmonary Disease: A Two-Sample Mendelian Randomization Study

Accumulating evidence has highlighted the importance of immune cells in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the understanding of the causal association between immunity and COPD remains incomplete due to the existence of confounding variables. In this study, we employed a two-sample Mendelian randomization (MR) analysis, utilizing the genome-wide association study database, to investigate the causal association between 731 immune-cell signatures and the susceptibility to COPD from a host genetics perspective. To validate the consistency of our findings, we utilized MR analysis results of lung function data to assess directional concordance. Furthermore, we employed MR-Egger intercept tests, Cochrane’s Q test, MR-PRESSO global test, and "leave-one-out" sensitivity analyses to evaluate the presence of horizontal pleiotropy, heterogeneity, and stability, respectively. Inverse variance weighting results showed that seven immune phenotypes were associated with the risk of COPD. Analyses of heterogeneity and pleiotropy analysis confirmed the reliability of MR results. These results highlight the interactions between the immune system and the lungs. Further investigations into their mechanisms are necessary and will contribute to inform targeted prevention strategies for COPD.

越来越多的研究证据凸显了免疫细胞在慢性阻塞性肺疾病（chronic obstructive pulmonary disease, COPD）发病机制中的重要作用。然而，由于混杂变量的存在，目前学界对免疫与COPD之间的因果关联仍缺乏全面认识。本研究采用两样本孟德尔随机化（two-sample Mendelian randomization, MR）分析方法，借助全基因组关联研究（genome-wide association study）数据库，从宿主遗传学视角探究了731种免疫细胞特征谱与COPD易感性之间的因果关联。为验证研究结果的一致性，本研究利用肺功能数据的MR分析结果，评估了效应方向的一致性。此外，本研究采用MR-Egger截距检验（MR-Egger intercept tests）、科克伦Q检验（Cochrane’s Q test）、MR-PRESSO全局检验（MR-PRESSO global test）以及「逐一剔除」（leave-one-out）敏感性分析，分别用以评估水平多效性、异质性与结果稳定性。逆方差加权（Inverse variance weighting）分析结果显示，共有7种免疫表型与COPD的发病风险存在关联。异质性与多效性分析结果证实了本研究MR分析结果的可靠性。本研究结果凸显了免疫系统与肺部之间的相互作用。未来仍需进一步探究二者相互作用的具体机制，这将为制定COPD的靶向预防策略提供理论支撑。