Evidence from observational studies suggests an association between chronic obstructive pulmonary disease (COPD) and lung cancer. The potential interactions between the immune system and the lungs may play a causative role in COPD and lung cancer and offer therapeutic prospects. However, the causal association and the immune-mediated mechanisms between COPD and lung cancer remain to be determined. We employed a two-sample Mendelian randomization (MR) approach to investigate the causal association between COPD and lung cancer. Additionally, we examined whether immune cell signals were causally related to lung cancer, as well as whether COPD was causally associated with immune cell signals. Furthermore, through two-step Mendelian randomization, we investigated the mediating effects of immune cell signals in the causal association between COPD and lung cancer. Leveraging publicly available genetic data, our analysis included 468,475 individuals of European ancestry with COPD, 492,803 individuals of European ancestry with lung cancer, and 731 immune cell signatures of European ancestry. Additionally, we conducted single-cell transcriptome sequencing analysis on COPD, lung cancer, and control samples to validate our findings. We found a causal association between COPD and lung cancer (odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.31–2.02, P-value < 0.001). We also observed a causal association between COPD and regulatory T cells (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.01–1.40, P-value < 0.05), as well as a causal association between regulatory T cells and lung cancer (odds ratio [OR] = 1.02, 95% confidence interval [CI] = 1.002–1.045, P-value < 0.05). Furthermore, our two-step Mendelian randomization analysis demonstrated that COPD is associated with lung cancer through the mediation of regulatory T cells. These findings were further validated through single-cell sequencing analysis, confirming the mediating role of regulatory T cells in the association between COPD and lung cancer. As far as we are aware, we are the first to combine single-celled immune cell data with two-sample Mendelian randomization. Our analysis indicates a causal association between COPD and lung cancer, with regulatory T cells playing an intermediary role.

中文翻译：

---

通过孟德尔随机化分析和 scRNA-seq 数据整合探索 Treg 介导的 COPD 风险与肺癌之间的关系

观察性研究的证据表明慢性阻塞性肺病 (COPD) 与肺癌之间存在关联。免疫系统和肺部之间的潜在相互作用可能在慢性阻塞性肺病和肺癌中发挥致病作用，并提供治疗前景。然而，慢性阻塞性肺病和肺癌之间的因果关系和免疫介导机制仍有待确定。我们采用两个样本孟德尔随机化 (MR) 方法来研究 COPD 与肺癌之间的因果关系。此外，我们还检查了免疫细胞信号是否与肺癌存在因果关系，以及慢性阻塞性肺病是否与免疫细胞信号存在因果关系。此外，通过两步孟德尔随机化，我们研究了免疫细胞信号在慢性阻塞性肺病和肺癌之间因果关系中的中介作用。利用公开的遗传数据，我们的分析包括 468,475 名欧洲血统患有慢性阻塞性肺病的个体、492,803 名欧洲血统患有肺癌的个体以及 731 个欧洲血统的免疫细胞特征。此外，我们对慢性阻塞性肺病、肺癌和对照样本进行了单细胞转录组测序分析，以验证我们的研究结果。我们发现 COPD 与肺癌之间存在因果关系（比值比 [OR] = 1.63，95% 置信区间 [CI] = 1.31–2.02，P 值 < 0.001）。我们还观察到 COPD 与调节性 T 细胞之间的因果关系（优势比 [OR] = 1.19，95% 置信区间 [CI] = 1.01–1.40，P 值 < 0.05），以及调节性 T 细胞之间的因果关系和肺癌（比值比 [OR] = 1.02，95% 置信区间 [CI] = 1.002–1.045，P 值 < 0.05）。此外，我们的两步孟德尔随机化分析表明，COPD 通过调节性 T 细胞的介导与肺癌相关。这些发现通过单细胞测序分析得到进一步验证，证实了调节性T细胞在慢性阻塞性肺病和肺癌之间的关联中的介导作用。据我们所知，我们是第一个将单细胞免疫细胞数据与两样本孟德尔随机化相结合的人。我们的分析表明 COPD 与肺癌之间存在因果关系，其中调节性 T 细胞发挥中介作用。