| 摘要: |
| 目的：基于多组学数据整合与孟德尔随机化（Mendelian randomization， MR）分析，系统探讨非酒精性脂肪肝（non-alcoholic fatty liver disease， NAFLD）因果相关的可成药靶点及分子机制，并预测靶向核心基因的中药。方法：整合公共组学与遗传数据库，获取可成药基因的表达数量性状位点（expression quantitative trait loci， eQTL）及疾病全基因组关联研究（genome-wide association study， GWAS）数据，开展双样本MR分析。通过异质性检验与多效性分析控制潜在偏倚，对显著基因进行基因本体（gene ontology， GO）功能和京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes， KEGG）通路富集分析、蛋白质-蛋白质相互作用（protein-protein interaction，PPI）分析及中药预测。结果：识别出27个与NAFLD显著因果关联的靶点基因，其中核糖体蛋白 L36（ribosomal protein L36，RPL36）、骨形态发生蛋白 8A（bone morphogenetic protein 8A，BMP8A）、细胞色素 P450 4F3（cytochrome P450 family 4 subfamily f member 3，CYP4F3）等为危险因素，血栓烷合酶 1（thromboxane synthase 1，TBXAS1）、膜联蛋白 A1（annexin A1，ANXA1）等为保护因素，主要参与B细胞受体信号、细胞凋亡、花生四烯酸代谢与白细胞介素-17（interleukin-17， IL-17）等通路。靶点互作网络揭示半胱天冬蛋白酶 3（Caspase 3，CASP3）、糖原合成酶激酶 3β（glycogen synthase kinase 3 Beta，GSK3β）、胞外 5'- 核苷酸酶（5'-nucleotidase ecto，NT5E）、ANXA1、羟甲基胆色烷合酶（hydroxymethylbilane synthase，HMBS）、线粒体解偶联蛋白 2（uncoupling protein 2，UCP2）为核心节点。基于上述核心靶点，靶向映射获取中药100味，药性以寒、温、平为主，药味以苦、辛、甘为主，多归肝、脾、肺经，功效集中于清热、活血化瘀、利湿及补虚。结论：本研究揭示了NAFLD的关键靶点及其分子机制，构建了“靶点-中药”模型，可为个体化防治及中医药干预提供参考。 |
| 关键词: 非酒精性脂肪肝 多组学挖掘 孟德尔随机化 可成药靶点 中药预测 |
| DOI： |
|
|
| Target identification and traditional Chinese medicine prediction for nonalcoholic fatty liver disease: A study based on multi-omics data mining |
| MENG Yuanyuan,LU Donghe,LIN Bangtao,ZHANG Meng,JIANG Xiao,YUAN Yuan |
| (The First Clinical Medical College of Guangxi University of Chinese Medicine,Nanning 530023, Guangxi, China;International Zhuang Medicine Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530201, Guangxi, China;Key Laboratory of Liver and Spleen Viscera of Guangxi Traditional Chinese Medicine,Nanning 530200, Guangxi, China;Key Laboratory of Liver and Spleen Viscera of Guangxi Traditional Chinese Medicine,Nanning 530200, Guangxi, China;School of Public Health and Management, Guangxi University of Chinese Medicine, Nanning 530200,Guangxi, China) |
| Abstract: |
| Objective： To systematically investigate the causally related druggable targets for nonalcoholic fatty liver disease （NAFLD） and their molecular mechanisms based on multi-omics data integration and Mendelian randomization （MR） analysis, and to predict traditional Chinese medicine （TCM） drugs targeting the core genes. Methods： Public omics and genetic databases were integrated to obtain the expression quantitative trait loci of druggable genes and the genome-wide association studies data of the disease, and a two-sample MR analysis was performed. The tests for heterogeneity and pleiotropy analysis were used to control potential biases, and the gene ontology functional enrichment analysis, the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, the protein-protein interaction analysis, and TCM prediction were performed for the significant genes. Results： A total of 27 target genes with significant causal associations with NAFLD were identified, among which ribosomal protein L36 （RPL36）, bone morphogenetic protein 8A （BMP8A）, and cytochrome P450 family 4 subfamily F member 3 （CYP4F3） were risk factors, while thromboxane synthase 1 （TBXAS1） and annexin A1 （ANXA1） were protective factors. These genes were mainly involved in pathways such as B cell receptor signaling, cell apoptosis, arachidonic acid metabolism, and interleukin-17. The target interaction network showed that Caspase 3 （CASP3）, glycogen synthase kinase 3 beta （GSK3β）, 5'-nucleotidase ecto （NT5E）, ANXA1, hydroxymethylbilane synthase （HMBS）, and uncoupling protein 2 （UCP2） were core nodes. Based on these core targets, 100 TCM drugs were identified by target mapping, mainly with a cold, warm, or neutral nature and a bitter, pungent, or sweet taste, and they mainly entered the liver, spleen, and lung meridians. Their main functions included clearing heat, activating blood and resolving stasis, promoting diuresis, and tonifying deficiency. Conclusion： This study reveals the key targets of NAFLD and their molecular mechanisms and constructs a “target-TCM” model, which can provide a reference for individualized prevention and treatment and TCM intervention. |
| Key words: nonalcoholic fatty liver disease multi-omics data mining Mendelian randomization druggable targets traditional Chinese medicine prediction |
