全基因测序探索多系统萎缩患者外周血液中铁死亡相关核心基因及其药物靶点

Analysis of ferroptosis hub genes in the peripheral blood of patients with multiple system atrophy andtheir drug targets by whole genome sequencing

目的探讨多系统萎缩(MSA)患者血液中差异表达的铁死亡相关基因,寻找诊断和治疗的新方向。方法收集MSA患者血液标本进行高通量全基因测序分析,对数据进行整理并筛选差异表达的长链非编码RNA(lncRNAs)及信使RNA(mRNAs)基因。进一步筛选铁死亡相关基因后进行基因本体论(GO)富集分析并构建蛋白质-蛋白质相互作用(PPI)网络,使用Cytoscape的MCODE插件筛选关键基因模块。构建铁死亡相关竞争性内源性RNA(ceRNA)网络,对网络中的mRNA基因进行基因药物关联性分析。最后利用PCR验证目标基因。结果共筛选出铁死亡相关mRNA基因34个。筛选核心模块和构建ceRNA网络发现2个网络中均存在MAPK14和MTF1基因。药物基因预测发现MAPK14具有众多药物治疗靶点。实时PCR结果表明MAPK14基因在MSA外周血液中显著上调,诊断性能良好。结论铁死亡相关基因在MSA患者外周血中存在差异表达,这些差异表达的基因可能与脂质代谢异常和氧化应激途径相关。其中,核心基因MAPK14在调控网络中发挥重要作用,并且是一个良好的潜在药物治疗靶点和诊断标志物。

Objective To analyze the differentially expressed ferroptosis genes in the blood of patients with multiple system atrophy(MSA),and to find a new direction for diagnosis and treatment.Methods Blood samples were collected from patients with MSA and subjected to high-throughput whole-genome sequencing analysis.The data were processed,and differentially expressed lncRNA and mRNAs genes were screened.Ferroptosis genes were further screened for gene ontology(GO)enrichment analysis and protein-protein interaction network construction.The MCODE plugin in Cytoscape was used to screen key gene modules.A ferroptosis competing endogenous RNA(ceRNA)network was constructed,and gene-drug association analysis was performed on the mRNAs genes in the network.Results A total of 34 ferroptosis mRNAs genes were identified.Hub modules and ceRNA network construction revealed that both networks contained MAPK14 and MTF1.Predictive drug gene analysis revealed that MAPK14 had numerous drug treatment targets.PCR results showed that MAPK14 mRNA expression was significantly upregulated in MSA group compared with healthy control group.Conclusion Ferroptosis genes are differentially expressed in the peripheral blood of patients with MSA,and these differentially expressed genes may be related to abnormal lipid metabolism and oxidative stress pathways.Among these,the hub gene MAPK14 may play an important role in the regulatory network and is an excellent potential drug therapeutic target and diagnostic marker.