目的 基于“见肾之病，知肾传心”理论，采用孟德尔随机化（Mendelian randomization，MR）方法探讨估算肾小球滤过率（estimate glomerular filtration rate，eGFR）与冠状动脉疾病（coronary artery disease，CAD）之间的遗传因果关系，并预测其潜在的中药干预策略。方法 从IEU OpenGWAS数据库获取eGFR与CAD的全基因组关联研究（genome-wide association studies，GWAS）数据，主要利用R软件TwoSampleMR包进行MR分析及结果的稳健性评估。通过Ensembl数据库预测工具变量的邻近基因（instrumental variable nearby genes，IVNGs），基于IVNGs进行功能富集分析，并分别借助比较毒性基因组学数据库（Comparative Toxicogenomics Database，CTD）和中药化学成分数据库（Database of Chemical Ingredients of Traditional Chinese Medicine，ITCM）预测相关化学成分及潜在中药。采用古今医案云平台（V2.3.9）对中药进行统计分析，以探讨其理法方药特点。结果 MR逆方差加权（inverse variance weighted，IVW）分析显示eGFR与CAD存在负向因果关联（β＝-0.231，P＝1.863×10^-5）。稳健性分析未发现显著异质性及水平多效性。富集分析提示相关机制主要涉及胰岛素分泌、钙离子信号及依赖环磷酸鸟苷（cyclic guanosine monophosphate，cGMP）的蛋白激酶（cyclic guanosine monophosphate-protein kinase G，cGMP-PKG）信号通路。中药聚类分析显示，前40味高频中药可分为5大类，其药性以平为主，温、寒次之；药味以苦为主，甘、辛次之；归经以肝为主，肺、脾、胃次之；功效以清热为主，祛湿及补虚次之。经典名方识别显示，前20味中药中黄芪、炙甘草、人参、陈皮、柴胡和白术为核心药物，相关方剂包括补中益气汤、升阳益胃汤、香砂六君子汤、完带汤和参苓白术散等。结论 在“见肾之病，知肾传心”理论指导下，证实eGFR与CAD存在负向遗传因果关系，其机制可能涉及胰岛素分泌、钙离子信号及cGMP-PKG信号通路。结合中药预测结果，初步探讨了中医药干预eGFR相关CAD的辨证思路及现存不足。

Objective Based on the theory of “seeing kidney disease, knowing it may affect the heart”, this study employed Mendelian randomization (MR) to explore the genetic causal relationship between estimated glomerular filtration rate (eGFR) and coronary artery disease (CAD), and to predict potential Chinese herbal interventions. Methods Genome-wide association study (GWAS) data for eGFR and CAD were obtained from the IEU OpenGWAS database. MR analysis and robustness evaluation were primarily conducted using the TwoSampleMR package in R. Instrumental variable nearby genes (IVNGs) were predicted via the Ensembl database. Functional enrichment analysis was performed based on IVNGs, and related chemical components and potential Chinese herbs were predicted using the Comparative Toxicogenomics Database (CTD) and the database of chemical Ingredients of Traditional Chinese Medicine (ITCM) respectively. The Ancient and Modern Medical Case Cloud Platform (V2.3.9) was used for statistical analysis of herbs to investigate their characteristics of principles, methods, formulas, and applications in treatment. Results Inverse variance weighted (IVW) analysis in MR indicated a negative causal association between eGFR and CAD (β = -0.231, P = 1.863 × 10⁻⁵). Robustness analysis showed no significant heterogeneity or horizontal pleiotropy. Enrichment analysis suggested that the mechanisms primarily involve insulin secretion, calcium ion signaling, and cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathways. Herbal cluster analysis revealed that the top 40 high-frequency herbs could be categorized into five major types. Their properties were mainly neutral, followed by warm and cold, flavors were predominantly bitter, followed by sweet and pungent, meridian tropism was primarily liver, followed by lung, spleen, and stomach, efficacy was mainly clearing heat, followed by eliminating dampness and tonifying deficiency. Classical formula identification based on the top 20 herbs highlighted six core herbs: Huangqi (Astragali Radix), Zhigancao (Glycyrrhizae Radix et Rhizoma Praeparata cum Melle), Renshen (Ginseng Radix et Rhizoma), Chenpi (Citri Reticulatae Pericarpium), Chaihu (Bupleuri Radix), and Baizhu (Atractylodis Macrocephalae Rhizoma). Related classical formulas included Buzhong Yiqi Decoction, Shengyang Yiwei Decoction, XiangshaLiujunzi Decoction, Wandai Decoction, and Shenling Baizhu Powder, among others. Conclusion Guided by the theory of “seeing kidney disease, knowing it may affect the heart”, this study confirmed a negative genetic causal relationship between eGFR and CAD, potentially mediated through insulin secretion, calcium signaling, and cGMP-PKG signaling pathways. Based on herbal predictions, the study preliminarily discusses the syndrome differentiation ideas and current limitations of traditional Chinese medicine in intervening in CAD related to eGFR.

R285

中国中医科学院西苑医院院内课题临床科研一体化平台建设项目(XYZX0405-22)