目的 基于“聚于胃，关于肺”理论，通过孟德尔随机化（Mendelian randomization，MR）分析探讨胃食管反流病（gastro-esophageal reflux disease，GERD）与慢性阻塞性肺疾病（chronic obstructive pulmonary disease，COPD）的遗传因果关系，并预测可干预GERD相关性COPD的潜在中药。方法 从IEU Open GWAS数据库获取GERD与COPD的全基因组关联研究数据集，采用双向MR分析评估二者的因果关系，并进行系列质量控制。随后，通过Ensembl数据库提取工具变量邻近基因，并利用功能富集分析探索GERD影响COPD发生风险的潜在机制。进而，对上述邻近基因进行蛋白质-蛋白质互作（protein-protein interaction，PPI）分析，以筛选参与该过程的核心基因。通过毒性与基因比较数据库（Comparative Toxicogenomics Database，CTD）和Coremine Medical数据库分别对潜在干预化学成分及中药进行预测，并对中药的药性功用信息进行统计分析。采用CytoNCA插件筛选核心中药，并进行中药成分与核心基因的分子对接初步佐证预测结果。结果 正向MR分析提示，GERD与COPD发病风险显著增加存在因果关联；质量控制结果证实该结果稳健。反向MR分析未发现COPD对GERD存在因果关联的证据。共获取到135个工具变量邻近基因，主要富集在核因子κB（nuclear factor-κB，NF-κB）信号转导的调控、白细胞介素-17（interleukin-17，IL-17）信号通路、肿瘤坏死因子（tumor necrosis factor，TNF）信号通路、磷脂酰肌醇-3-羟激酶（phosphatidylinositol-3-hydroxykinase，PI3K）/蛋白激酶B（protein kinase B，Akt）信号通路、自然杀伤细胞介导的细胞毒性等生物学途径。将PPI分析筛选到的前5个基因确定为核心基因。利用CTD及Coremine Medical数据库共预测到163个化学成分和167味中药。中药四气以寒、温为主，平次之；五味以苦、甘、辛为主；归经以肺经为主，肝、脾、胃经次之；功效以补虚、化痰止咳平喘为主，清热、解表、理气次之。CytoNCA计算后，筛选出关键中药麻黄、白果、半夏、陈皮、桑白皮、甘草、干姜、生姜、黄芪、人参、茯苓、白术，分子对接显示核心基因与中药关键成分具有较好的结合能力。结论 基于“聚于胃，关于肺”理论，不仅从遗传学视角证实了GERD是COPD的致病风险因素，亦揭示了其潜在机制与NF-κB、IL-17、TNF、PI3K-Akt等炎症与免疫信号通路密切相关，预测的中药治法以补虚、化痰止咳平喘为主。

Objective To explore the genetic causal relationship between gastro-esophageal reflux disease (GERD) and chronic obstructive pulmonary disease (COPD) by Mendelian randomization (MR) analysis based on the theory of “gather in stomach and focus on lung”, and to predict potential Chinese herbal medicines that may intervene in GERD-related COPD. Methods The genome-wide association study (GWAS) datasets for GERD and COPD were obtained from the IEU Open GWAS database. A bidirectional two-sample Mendelian randomization (MR) analysis was applied to evaluate the causal relationship between the two conditions, followed by a series of quality control procedures. Subsequently, proximal genes of the instrumental variables were extracted using the Ensembl database, and functional enrichment analysis was performed to explore the potential mechanisms by which GERD influences COPD risk. Furthermore, protein-protein interaction (PPI) analysis was conducted on these proximal genes to identify core genes involved in this process. Potential intervention chemical components and Chinese herbal medicines were predicted using the Comparative Toxicogenomics Database (CTD) and the Coremine Medical database, respectively, and statistical analysis was carried out on the medicinal properties and functions of the identified herbs. The CytoNCA plugin was used to screen core Chinese herbal medicines, and molecular docking of traditional Chinese medicine components with core genes to preliminarily verify the prediction results. Results Forward MR analysis indicated that GERD was causally associated with a significantly increased risk of COPD onset; quality control results confirmed the robustness of this finding. Reverse MR analysis did not reveal evidence supporting a causal effect of COPD on GERD. A total of 135 proximal genes of the instrumental variables were identified, which were primarily enriched in biological pathways such as the regulation of Nuclear Factor-Kappa B (NF-κB) signal transduction, the Interleukin-17 (IL-17) signaling pathway, the Tumor Necrosis Factor (TNF) signaling pathway, the Phosphatidylinositol 3-Kinase-Protein Kinase B (PI3K-Akt) signaling pathway, and natural killer cell-mediated cytotoxicity. The top five genes identified through PPI analysis were determined as core genes. Using the CTD and Coremine Medical databases, 163 chemical components and 167 Chinese herbal medicines were predicted. Statistical analysis of the medicinal properties of the herbs showed that among the Four Natures, cold and warm properties predominated, followed by neutral; among the five flavors, bitter, sweet, and pungent were most common; the primary meridian tropism was the lung meridian, followed by the liver, spleen, and stomach meridians; in terms of functions, tonifying deficiency and resolving phlegm, relieving cough and asthma were primary, followed by clearing heat, relieving exterior syndrome, and regulating qi. After calculation with CytoNCA, key herbs were screened out, including Mahuang (Ephedrae Herba), Baiguo (Ginkgo Semen), Banxia (Pinelliae Rhizoma), Chenpi (Citri Reticulatae Pericarpium), Sangbaipi (Mori Cortex), Gancao (Glycyrrhizae Radix et Rhizoma), Ganjiang (Zingiberis Rhizoma), Shengjiang (Zingiberis Rhizoma Recens), Huangqi (Astragali Radix), Renshen (Ginseng Radix et Rhizoma), Fuling (Poria), and Baizhu (Atractylodis Macrocephalae Rhizoma). Molecular docking demonstrated favorable binding affinity between the core genes and the key components of these Chinese herbal medicines. Conclusion Based on the theory of "accumulation in the stomach and its connection with the lungs," this study not only confirms from a genetic perspective that GERD is a risk factor for COPD, but also reveals that its potential mechanisms are closely associated with inflammatory and immune signaling pathways such as NF-κB, IL-17, TNF, and PI3K-Akt. The predicted Chinese herbal treatment strategies primarily focus on tonifying deficiency, resolving phlegm, relieving cough, and calming asthma.

Q811.4;R285

国家自然科学基金项目（82274462）；国家自然科学基金项目（82575036）；北京市自然科学基金项目（7232284）；国家中医药管理局第五批全国中医临床优秀人才研修项目（国中医药人教函[2022]1号）；北京市中医药管理局北京中医药新时代125工程（京中医药科字[2025]2号）；北京中医药大学第三附属医院精诚人才计划（京中三院人[2025]4号）