血管紧张素转换酶2抑制性突变相关炎症反应与干预药物的组学分析及其对新型冠状病毒肺炎的意义

Omics analysis of angiotensin converting enzyme 2 inhibitory mutation-related inflammatory response and intervention drugs and its significance on corona virus disease 2019

目的分析血管紧张素转换酶2(angiotensin converting enzyme 2,ACE2)抑制性突变相关炎症机制及其潜在干预药物,为治疗新型冠状病毒肺炎(COVID-19)提供参考。方法从肿瘤基因图谱(the cancer genome atlas,TCGA)数据库筛选具有ACE2突变的肺腺癌数据,采用R程序语言edgeR包与clusterProfiler包对数据进行差异分析、基因本体学(gene ontology,GO)功能富集分析与京都基因和基因组数据库(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析。使用String在线分析网站对差异基因进行蛋白质-蛋白质相互作用(protein-protein interaction,PPI)网络分析,筛选出核心基因。应用表观精准治疗预测平台(Epigenomic Precision Medicine Prediction Platform,EpiMed)对关键基因进行多组学关联分析和药物预测。结果共得到差异基因1005个,其中表达上调91个,下调914个。GO富集71条,其中生物学进程45条,细胞组分16条,分子功能10条。KEGG通路共富集13条,主要富集在炎症通路、病毒感染性疾病、转录调控、药物代谢和蛋白质消化吸收相关通路。PPI网络分析共得到252个蛋白质,H2A簇状组蛋白16、H3簇状组蛋白2、H3簇状组蛋白7、H3簇状组蛋白11、H3簇状组蛋白3、H2B簇状组蛋白3、H2B簇状组蛋白6、H4簇状组蛋白2、H1-4接头组蛋白、H2A簇状组蛋白4为筛选出的10个核心基因。α干扰素、白藜芦醇、塞来昔布、鱼腥草、连翘、地塞米松、白头翁、肿瘤坏死因子α抑制剂、甘草和泛昔洛韦可能是治疗ACE2突变相关炎症的药物。结论ACE2抑制性突变相关炎症与COVID-19发病机制类似,通过激活促进丝裂原活化蛋白激酶、Janus激酶/信号转导及转录激活因子和哺乳动物雷帕霉素靶蛋白等炎症通路导致疾病发生,白藜芦醇、干扰素、塞来昔布等药物可能对COVID-19具有潜在治疗作用。

Objective To analyze the inflammatory mechanism and potential intervention drugs related to angiotensin converting enzyme 2(ACE2)inhibitory mutations in order to provide reference for the treatment of corona virus disease 2019(COVID-19).Methods The data of lung adenocarcinoma with ACE2 mutations were screened from the cancer genome atlas(TCGA)database.The data were analyzed by R program language edgeR package and cluster Profiler package,gene ontology(GO)functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis.Using String online analysis website for protein-protein interaction(PPI)network analysis,screening out the core genes,and finally using the Epigenomic Precision Medicine Prediction Platform(EpiMed)for multi-group association analysis of key genes,and drug candidates prediction.Results A total of 1005 differential genes were obtained,of which 91 were up-regulated and 914 down-regulated.A total of 71 GO were enriched,including 45 items related to biological processes,16 items related to cell components,and 10 items related to molecular function.A total of 13 KEGG pathways were enriched,mainly in inflammatory pathways,various viral infectious diseases,transcriptional regulation,drug metabolism and protein digestion and absorption pathways.The differentially expressed genes were introduced into String online analysis website for PPI network analysis,a total of 252 proteins were obtained,and 10 core genes were H2A clustered histone 16(HIST1H2AL),H3 clustered histone 2(HIST1H3B),H3 clustered histone 7(HIST1H3F),H3 clustered histone 11(HIST1H3I),H3 clustered histone 3(HIST1H3C),H2B clustered histone 3(HIST1H2BB),H2B clustered histone 6(HIST1H2BI),H4 clustered histone 2(HIST1H4B),H1-4 linker histone(HIST1H1E),H2A clustered histone 4(HIST1H2AB).Interferon-α,resveratrol,celecoxib,heartleaf houttuynia herb,weeping forsythia capsule,dexamethasone,Chinese pulsatilla root,tumor necrosis factor-αinhibitors,liquorice root and famciclovir might be drugs for the treatment of ACE2 mutation-related inflammation.Conclusions Inflammation associated with ACE2 inhibitory mutations is similar to the pathogenesis of COVID-19,which could lead to disease by promoting the activation of inflammatory pathways such as mitogen-activated protein kinase(MAPK),the Janus kinase signal transducer and activator of transcription(JAK/STAT),mammalian target of rapamycin(mTOR).Celecoxib,interferon and resveratrol may have the potential therapeutic effects on COVID-19.