Gene dysfunction and immune cell infiltration play an essential role in the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). We aimed to investigate the immune landscape and novel differentially expressed genes (DEGs) of IPAH. In addition, potential druggable molecular targets for IPAH were also explored. In this study, the GSE117261 dataset was reanalyzed to explore the immune landscape and hub DEGs of IPAH. Lasso Cox regression analysis and receiver operating characteristic curve analysis were performed to detect the predictive value of IPAH. Additionally, the underlying drug targets for IPAH treatment were determined by drug-gene analysis. IPAH was significantly associated with the transforming growth factor-β (TGF-β) signaling pathway and Wnt signaling pathway as well as energetic metabolism dysfunction. We identified 31 upregulated and 39 downregulated DEGs in IPAH patients. Six hub genes, namely, SAA1, CCL5, CXCR1, CXCR2, CCR1, and ADORA3, were related to IPAH pathogenesis regardless of sex differences. Prediction model analysis showed that the area under the curve values of the hub DEGs except CXCR2 were all above 0.9 for distinguishing IPAH patients. In addition, the relative proportions of 5 subtypes of immune cells, namely, CD8+ T cells, CD4+ memory resting T cells, γ delta T cells, M1 macrophages, and resting mast cells, were significantly upregulated in the IPAH samples, while 6 subtypes of immune cells, namely, CD4+ naive T cells, resting NK cells, monocytes, M0 macrophages, activated mast cells, and neutrophils, were downregulated. Additionally, a total of 17 intersecting drugs targeting 5 genes, CCL5, CXCR1, CXCR2, CCR1, and ADORA3, were generated as potential druggable molecular targets for IPAH. Our study revealed the underlying correlations between genes and immune cells in IPAH and demonstrated for the first time that SAA1, CCL5, CXCR1, CCR1, and ADORA3 may be novel genetic targets for IPAH.

中文翻译：

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通过微阵列基因表达数据集再分析鉴定特发性肺动脉高压的潜在风险基因和免疫景观

基因功能障碍和免疫细胞浸润在特发性肺动脉高压 (IPAH) 的发病机制中起重要作用。我们旨在研究 IPAH 的免疫景观和新型差异表达基因 (DEG)。此外，还探索了 IPAH 的潜在可成药分子靶点。在这项研究中，重新分析了 GSE117261 数据集以探索 IPAH 的免疫景观和枢纽 DEG。采用Lasso Cox回归分析和受试者工作特征曲线分析检测IPAH的预测价值。此外，IPAH 治疗的潜在药物靶点是通过药物基因分析确定的。IPAH与转化生长因子-β（TGF-β）信号通路和Wnt信号通路以及能量代谢功能障碍显着相关。我们在 IPAH 患者中鉴定了 31 个上调和 39 个下调的 DEG。六个中枢基因，即 SAA1、CCL5、CXCR1、CXCR2、CCR1 和 ADORA3，与 IPAH 发病机制无关，与性别差异无关。预测模型分析表明，除CXCR2外，hub DEGs的曲线下面积均在0.9以上，用于区分IPAH患者。此外，5种免疫细胞亚型，即CD8+ T细胞、CD4+记忆静息T细胞、γδT细胞、M1巨噬细胞和静息肥大细胞的相对比例在IPAH样本中显着上调，而6种亚型的免疫细胞，即 CD4+ 幼稚 T 细胞、静息 NK 细胞、单核细胞、M0 巨噬细胞、活化的肥大细胞和中性粒细胞，被下调。此外，共有 17 种交叉药物靶向 5 个基因，CCL5、CXCR1、CXCR2、CCR1 和 ADORA3，作为 IPAH 的潜在可药物分子靶标产生。我们的研究揭示了 IPAH 中基因和免疫细胞之间的潜在相关性，并首次证明 SAA1、CCL5、CXCR1、CCR1 和 ADORA3 可能是 IPAH 的新遗传靶点。