Xu Wei-Ming, Yang Kuo, Jiang Li-Jie, Hu Jing-Qing, Zhou Xue-Zhong
Research Centre for Disease and Syndrome, Institute of Basic Theory for Traditional Chinese Medicine, China Academy of Chinese Medicine Sciences, Beijing, China.
School of Computer and Information Technology and Beijing Key Lab of Traffic Data Analysis and Mining, Beijing Jiaotong University, Beijing, China.
Front Physiol. 2018 Jan 22;9:7. doi: 10.3389/fphys.2018.00007. eCollection 2018.
Ischemic heart disease (IHD) has been the leading cause of death for several decades globally, IHD patients usually hold the symptoms of phlegm-stasis cementation syndrome (PSCS) as significant complications. However, the underlying molecular mechanisms of PSCS complicated with IHD have not yet been fully elucidated. Network medicine methods were utilized to elucidate the underlying molecular mechanisms of IHD phenotypes. Firstly, high-quality IHD-associated genes from both human curated disease-gene association database and biomedical literatures were integrated. Secondly, the IHD disease modules were obtained by dissecting the protein-protein interaction (PPI) topological modules in the String V9.1 database and the mapping of IHD-associated genes to the PPI topological modules. After that, molecular functional analyses (e.g., Gene Ontology and pathway enrichment analyses) for these IHD disease modules were conducted. Finally, the PSCS syndrome modules were identified by mapping the PSCS related symptom-genes to the IHD disease modules, which were further validated by both pharmacological and physiological evidences derived from published literatures. The total of 1,056 high-quality IHD-associated genes were integrated and evaluated. In addition, eight IHD disease modules (the PPI sub-networks significantly relevant to IHD) were identified, in which two disease modules were relevant to PSCS syndrome (i.e., two PSCS syndrome modules). These two modules had enriched pathways on Toll-like receptor signaling pathway (hsa04620) and Renin-angiotensin system (hsa04614), with the molecular functions of angiotensin maturation (GO:0002003) and response to bacterium (GO:0009617), which had been validated by classical Chinese herbal formulas-related targets, IHD-related drug targets, and the phenotype features derived from human phenotype ontology (HPO) and published biomedical literatures. A network medicine-based approach was proposed to identify the underlying molecular modules of PSCS complicated with IHD, which could be used for interpreting the pharmacological mechanisms of well-established Chinese herbal formulas (). In addition, these results delivered novel understandings of the molecular network mechanisms of IHD phenotype subtypes with PSCS complications, which would be both insightful for IHD precision medicine and the integration of disease and TCM syndrome diagnoses.
几十年来，缺血性心脏病（IHD）一直是全球主要的死亡原因，IHD患者通常伴有痰瘀互结证（PSCS）这一显著并发症。然而，PSCS合并IHD的潜在分子机制尚未完全阐明。本研究运用网络医学方法来阐明IHD表型的潜在分子机制。首先，整合来自人工整理的疾病-基因关联数据库和生物医学文献的高质量IHD相关基因。其次，通过剖析String V9.1数据库中的蛋白质-蛋白质相互作用（PPI）拓扑模块以及将IHD相关基因映射到PPI拓扑模块来获得IHD疾病模块。之后，对这些IHD疾病模块进行分子功能分析（如基因本体论和通路富集分析）。最后，通过将PSCS相关症状基因映射到IHD疾病模块来识别PSCS综合征模块，并通过已发表文献中的药理学和生理学证据进一步验证。共整合并评估了1056个高质量的IHD相关基因。此外，鉴定出八个IHD疾病模块（与IHD显著相关的PPI子网），其中两个疾病模块与PSCS综合征相关（即两个PSCS综合征模块）。这两个模块在Toll样受体信号通路（hsa04620）和肾素-血管紧张素系统（hsa04614）上有富集通路，具有血管紧张素成熟（GO:0002003）和对细菌的反应（GO:0009617）的分子功能，这些已通过经典中药配方相关靶点、IHD相关药物靶点以及来自人类表型本体（HPO）和已发表生物医学文献的表型特征得到验证。提出了一种基于网络医学的方法来识别PSCS合并IHD的潜在分子模块，该方法可用于解释成熟中药配方的药理机制。此外，这些结果为IHD合并PSCS并发症的表型亚型的分子网络机制提供了新的认识，这对于IHD精准医学以及疾病与中医证候诊断的整合都具有重要意义。
