中国药学(英文版) ›› 2022, Vol. 31 ›› Issue (12): 912-927.DOI: 10.5246/jcps.2022.12.077
姚昆鹏1,2, 张道平1,2, 刘起立1,2, 蔡虎志2, 陈青扬2,*(), 陈新宇1,2,*()
收稿日期:
2022-03-23
修回日期:
2022-03-28
接受日期:
2022-06-27
出版日期:
2022-12-27
发布日期:
2022-12-27
通讯作者:
陈青扬, 陈新宇
作者简介:
基金资助:
Kunpeng Yao1,2, Daoping Zhang1,2, Qili Liu1,2, Huzhi Cai2, Qingyang Chen2,*(), Xinyu Chen1,2,*()
Received:
2022-03-23
Revised:
2022-03-28
Accepted:
2022-06-27
Online:
2022-12-27
Published:
2022-12-27
Contact:
Qingyang Chen, Xinyu Chen
摘要:
采用Gene Expression Omnibus (GEO)数据集联合机器学习研究急性心肌梗死(acute myocardial infarction, AMI)的差异基因, 并预测具有调控作用的潜在成分及中药。从GEO数据库下载AMI的人类全基因组数据集(GSE66360和GSE61145), 以GSE66360作为测试集, 通过R语言的normalize Between Arrays包进行校正后, 再调用limma包获取差异基因(DEGs), 对DEGs作Gene Ontology (GO)、Kyoto Encyclopedia of Genes and Genomes (KEGG)、Disease Ontology (DO)富集分析; 采用SVM及随机森林树法筛选特征基因, 利用GSE61145数据集对得出的特征基因进行验证; 通过CTD数据库找到AMI特征基因所对应的中药成分, 利用Coremine数据库映射中药成分所对应的中药, 并依据《中药大辞典》、《中华本草》、《中国药典》等对所得中药的频次、四气、五味、归经进行汇总。通过对GSE66360数据集进行分析, 得到317个差异基因, 其中306个上调, 11个下调, GO和KEGG富集分析显示AMI的差异基因主要涉及中性粒细胞介导的炎症和免疫反应、脂代谢异常、脂质和动脉粥样硬化相关通路等, DO富集分析表明差异基因与动脉硬化性心血管疾病、肺部疾患等密切相关。通过SVM及随机森林树法得到6个特征基因: ZFP36、GADD45A、PELI1、METRNL、MMP9、CXCL16。CTD映射到成分97种, Coremine数据库映射到中药824味, 汇总后发现治疗AMI的中药以甘、苦、温为主, 多归于脾、胃、肝经。经汇总后, 调控AMI的特征基因(ZFP36、GADD45A、PELI1、METRNL、MMP9、CXCL16)成分主要有苯并[a]芘, 四氯二苯二氧芑, 对乙酰氨基酚等, 中药有茶树根、郁金、人参等, 其性味为甘、苦、温, 归经多为脾、胃、肝经。
Supporting:
姚昆鹏, 张道平, 刘起立, 蔡虎志, 陈青扬, 陈新宇. 整合生物信息学鉴定与分析急性心肌梗死的特征基因及潜在中药预测[J]. 中国药学(英文版), 2022, 31(12): 912-927.
Kunpeng Yao, Daoping Zhang, Qili Liu, Huzhi Cai, Qingyang Chen, Xinyu Chen. Integrating bioinformatics to identify and analyze feature genes of acute myocardial infarction and potential Chinese medicine prediction[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(12): 912-927.
Figure 2. GSE66360 dataset pre-processing. Note. Figures 2A–B is the schematic diagram of the GSE66360 dataset before and after correction, and the corrected dataset has a good consistency. Figure 2C is the differential gene volcano map of GSE66360; Figure 2D is the differential gene heat map of GSE66360.
Figure 3. GO/KEGG/DO enrichment analysis of differential genes. Note. Figure 3A–C shows the GO, KEGG, and DO enrichment analysis of the differential genes in order. In GO string plot, the gene name is on the left side, and the GO entry is on the right side. The more GO entries corresponding to a gene indicate that the gene mediates AMI through multiple mechanisms, and the legend in the lower-left corner represents the logFC value of the gene. In KEGG plot, the inner concentric circles represent the gene, the outer concentric circles represent the signaling pathways enriched by the gene, and the legend in the lower-left corner represents the logFC value of the gene. In DO bar plot, the vertical coordinate is the disease in which the gene is enriched, and the horizontal coordinate is the number of enriched genes corresponding to the disease.
Figure 4. SVM and random forest tree to filter feature genes. Note. Figure 4A shows the schematic diagram of SVM. The horizontal coordinate is the number of genes, and the vertical coordinate is the error of cross-validation. When the number of genes is 10, the error is the smallest, so 10 feature genes are derived. Figure 4B shows the schematic diagram of a random forest tree. The horizontal coordinate is the gene importance score, and the vertical coordinate is the gene name. The gene ranked in top 30 is selected as the feature gene. Figure 4C shows the feature genes screened by SVM and random forest tree gene intersection Venn diagram.
Figure 5. Differential gene validation and ROC curve. Note. Figure 5A–F indicates the variability of target genes in the validation set, the horizontal coordinates indicate the normal group and the control group, and the vertical coordinates indicate the gene expression. Figure 5G–L shows the ROC curves of GSE66360, the horizontal coordinates indicate the False Positive Rate (FPR), and the vertical coordinates indicate the True Positive Rate (TPR). The larger the AUC, the higher the accuracy of the feature gene. Figure 5M–R shows the ROC curve of GSE61145.
Figure 6. "Feature gene-drug component-Chinese medicine" network diagram and Chinese medicine collation. Note. Figure 6A is a network diagram of the "signature gene-drug component-Chinese medicine" for the top five Chinese herbal medicines, in which the red line represents the up-regulation relationship, the green line represents the down-regulation relationship, and the purple line represents the bidirectional regulation. The left inverted triangle represents the five feature genes, the middle concentric circles represent the components with regulatory effects on the feature genes, where the outer green circle represents the components with up-regulation, the red represents the components with down-regulation, the blue represents the components with bidirectional regulation, and the right diamond represents the Chinese herbal medicines mapped to the components (this paper only showed the mapping process of the top five Chinese herbal medicines). Figure 6B–D: radar diagrams of the four qi, the five flavors, and the attribute of potential Chinese medicines are shown in order, and the numbers represent the frequencies of their respective occurrences.
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