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通过生物信息学分析洞察糖尿病视网膜病变中血管内皮生长因子(VEGF)相关基因的失调

Insight into dysregulated VEGF-related genes in diabetic retinopathy through bioinformatic analyses.

作者信息

Wang Xiaoguang, He Xianglian, Li Zhen, Mu Tao, Pang Lin, Ma Weiguo, Hu Xuejun

机构信息

Ningxia Hui Autonomous Region People's Hospital, Ningxia Eye Hospital, No. 301 Zhengyuan North Street, Jinfeng District, Yinchuan City, 750004, Ningxia Hui Autonomous, China.

出版信息

Naunyn Schmiedebergs Arch Pharmacol. 2024 Dec 27. doi: 10.1007/s00210-024-03638-y.

Abstract

Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes mellitus. VEGF plays a pivotal role in the pathogenesis of DR. To characterize the VEGF-related genes in DR patients, the RNAseq dataset of DR and normal control were downloaded from the GEO database and analyzed using R package limma. The differentially expressed VEGFGs between DR and NC were identified, and their expression levels were verified through qRT-PCR and Western blotting. Enrichment analyses were performed to understand the key functions and involved pathways of DE-VEGFGs. A two-sample MR analysis was carried out to study the causal link between prostate cancer and DR. Next, we built a nomogram model to predict the risk of DR using the expression level of DE-VEGFGs. Additionally, we estimated the immune cell infiltration between clusters and calculated the correlation between DE-VEGFGs expression and immune cell infiltration in DR. The DGIdb database was used to identify potential target drug for DE-VEGFGs. Finally, we constructed a ceRNA regulation network with predictions from miRNA-mRNA interaction databases and miRNA-lncRNA interaction database. We identified six DE-VEGFGs that are involved in the regulation of the VEGF pathway. The two-sample MR analysis revealed a positive correlation between prostate cancer and the risk of DR. The nomogram which uses the DE-VEGFGs expression to predict the DR risk shows good performance based on the calibration curve and AUC value. Monocytes and T cells CD4 memory activated show different expression between DR and NC; meanwhile, these cell types were correlated with DE-VEGFGs. The drug-gene interaction network provides candidates for DR treatment, and the ceRNA regulation network suggests a potential biomarker for DR. Our study identified dysregulated VEGF-related genes in DR and emphasized their significance in the pathogenesis of DR. Additionally, our findings offer insights into their potential clinical predictive value, immune implications, targeting drug candidates, and regulatory network dynamics.

摘要

糖尿病视网膜病变(DR)是糖尿病常见的微血管并发症。血管内皮生长因子(VEGF)在DR的发病机制中起关键作用。为了表征DR患者中与VEGF相关的基因,从基因表达综合数据库(GEO数据库)下载了DR和正常对照的RNA测序数据集,并使用R包limma进行分析。鉴定了DR和正常对照之间差异表达的VEGFGs,并通过定量逆转录聚合酶链反应(qRT-PCR)和蛋白质免疫印迹法验证了它们的表达水平。进行富集分析以了解差异表达的VEGFGs的关键功能和涉及的信号通路。进行了两样本孟德尔随机化(MR)分析,以研究前列腺癌与DR之间的因果关系。接下来,我们构建了一个列线图模型,使用差异表达的VEGFGs的表达水平来预测DR的风险。此外,我们估计了不同簇之间的免疫细胞浸润,并计算了DR中差异表达的VEGFGs表达与免疫细胞浸润之间的相关性。利用药物基因相互作用数据库(DGIdb数据库)来鉴定差异表达的VEGFGs的潜在靶向药物。最后,我们根据微小RNA(miRNA)-信使核糖核酸(mRNA)相互作用数据库和miRNA-长链非编码核糖核酸(lncRNA)相互作用数据库的预测构建了一个竞争性内源RNA(ceRNA)调控网络。我们鉴定出六个参与VEGF信号通路调控的差异表达的VEGFGs。两样本MR分析显示前列腺癌与DR风险之间存在正相关。使用差异表达的VEGFGs表达来预测DR风险的列线图基于校准曲线和曲线下面积(AUC)值显示出良好的性能。单核细胞和CD4记忆激活T细胞在DR和正常对照之间表现出不同的表达;同时,这些细胞类型与差异表达的VEGFGs相关。药物-基因相互作用网络为DR治疗提供了候选药物,ceRNA调控网络提示了DR的潜在生物标志物。我们的研究确定了DR中失调的VEGF相关基因,并强调了它们在DR发病机制中的重要性。此外,我们的研究结果为它们的潜在临床预测价值、免疫影响、靶向候选药物和调控网络动态提供了见解。

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