Table_3_Identification of intrinsic genes across general hypertension, hypertension with left ventricular remodeling, and uncontrolled hypertension.xlsx

The purpose of the present article is to identify intrinsic genes across general hypertension (HT), hypertension with left ventricular remodeling (HT-LVR), and uncontrolled hypertension (UN-HT). In total, four microarray datasets (GSE24752, GSE75360, GSE74144, and GSE71994) were downloaded from the GEO database and were used to identify differentially expressed genes (DEGs), respectively. Furthermore, gene set enrichment analysis (GSEA) was utilized to screen for significantly enriched biological pathways across the four datasets above, respectively. Furthermore, weighted gene co-expression network analysis (WGCNA) and functional enrichment analysis were applied to screen out gene modules of interest and potential biological functions, respectively. Finally, a Metascape-based multiple gene list meta-analysis was used to investigate intrinsic genes at different stages of the progression of hypertension. A total of 75 DEGs (63 upregulated genes and 12 downregulated genes, GSE24752) and 23 DEGs (2 upregulated genes and 21 downregulated genes, GSE74144) were identified. However, there were few DEGs identified in GSE75360, GSE71994, and part of the GSE74144 datasets. GSEA and functional enrichment of gene module of interest have indicated that “Heme metabolism,” “TNF alpha/NFkB,” and “interferon alpha response signaling,” and MYC target v1/v2 were enriched significantly in different stages of hypertension progression. Significantly, findings from the multiple gene list meta-analysis suggested that FBXW4 and other 13 genes were unique to the hypertension group, and TRIM11 and other 40 genes were mainly involved in hypertension with the left ventricular remodeling group, while the other 18 genes including F13A1 significantly enriched in uncontrolled hypertension. Collectively, the precise switch of the “immune-metabolic-inflammatory” loop pathway was the most significant hallmark across different stages of hypertension, thereby providing a potential therapeutic target for uncontrolled hypertension treatment.

本研究旨在鉴定原发性高血压（general hypertension, HT）、伴左心室重构的高血压（hypertension with left ventricular remodeling, HT-LVR）以及未控制性高血压（uncontrolled hypertension, UN-HT）三类高血压中的固有基因。本研究从GEO数据库下载了共计4个微阵列数据集（GSE24752、GSE75360、GSE74144及GSE71994），分别用于鉴定差异表达基因（differentially expressed genes, DEGs）。此外，本研究采用基因集富集分析（gene set enrichment analysis, GSEA）分别对上述4个数据集进行显著富集生物通路的筛选。进一步，本研究分别通过加权基因共表达网络分析（weighted gene co-expression network analysis, WGCNA）及功能富集分析，筛选出目标基因模块与潜在生物学功能。最后，本研究采用基于Metascape的多基因列表荟萃分析，探究高血压进程不同阶段的固有基因。经鉴定，GSE24752数据集中共获得75个差异表达基因（其中上调基因63个、下调基因12个），GSE74144数据集中共获得23个差异表达基因（其中上调基因2个、下调基因21个）。但在GSE75360、GSE71994及部分GSE74144数据集中，仅鉴定得到少量差异表达基因。基因集富集分析与目标基因模块功能富集分析结果显示，血红素代谢、肿瘤坏死因子α/核因子κB、Ⅰ型干扰素应答信号通路及MYC靶标v1/v2在高血压进程的不同阶段均显著富集。尤为重要的是，多基因列表荟萃分析结果显示，FBXW4等13个基因为高血压组特有基因，TRIM11等40个基因主要富集于伴左心室重构的高血压组，而包括F13A1在内的其余18个基因则显著富集于未控制性高血压组。综上，"免疫-代谢-炎症"环路通路的精准调控切换是高血压不同病程阶段最显著的特征，该发现可为未控制性高血压的治疗提供潜在治疗靶点。