Objective: To investigate the gene expression characteristics of peripheral blood mononuclear cells from patients with high altitude pulmonary hypertension (HAPH) in Naxi residents living in Lijiang, Yunnan, and to explore the underlying pathogenesis and value for potential drug selection. Methods: This is a case-control study. Six patients with HPAH (HPAH group) and 4 normal subjects (control group) were selected from the Naxi residents who originally lived in Lijiang, Yunnan Province. The general clinical data of the two groups were collected, and the related indexes of pulmonary artery pressure were collected. Peripheral blood mononuclear cells of the subjects were collected for RNA sequencing. The differences on gene expression, regulatory network of transcription factors and drug similarity between the two groups were compared. The results were compared with the public data of idiopathic pulmonary arterial hypertension (IPAH). Biological processes and signal pathways were analyzed and compared between HPAH and IPAH patients. Results: The age of 6 patients with HAPH was (68.1±8.3) years old, and there were 2 males (2/6). The age of 4 subjects in the control group was (62.3±10.9) years old, and there were 2 males (2/4). Tricuspid regurgitation velocity, tricuspid pressure gradient and pulmonary systolic pressure in HAPH group were significantly higher than those in control group (all P<0.05). The results of RNA sequencing showed that compared with the control group, 174 genes were significantly upregulated and 169 genes were downregulated in peripheral blood mononuclear cells of HAPH group. These differentially expressed genes were associated with 220 biological processes, 52 molecular functions and 23 cell components. A total of 21 biological processes and 2 signal pathways differed between HPAH and IPAH groups, most of which were related to inflammation and immune response. ZNF384, SP1 and STAT3 were selected as highly correlated transcription factors by transcription factor prediction analysis. Trichostatin A and vorinostat were screened out as potential drugs for the treatment of HAPH by drug similarity analysis. Conclusions: There are significant differences in gene expression in peripheral blood monocytes between HAPH patients and normal population, and inflammation and immune dysfunction are the main pathogenic factors. Trichostatin A and Vorinostat are potential drugs for the treatment of HAPH.
目的： 探索高原性肺高血压（HAPH）患者外周血单个核细胞基因表达特征，挖掘可能的发病机制和潜在的治疗药物。 方法： 本研究为现况性病例对照研究，从世居云南省丽江市的纳西人群中，采用超声心动图筛选出6例HAPH受试者及4例正常对照，作为HAPH组和对照组。收集两组受试者的一般临床资料并采集肺动脉压力相关指标。采集受试者的外周血单个核细胞进行RNA测序，对比两组间基因表达差异，进行富集分析、转录因子基因表达调控网络构建及药物相似性分析；并与特发性肺高血压（IPAH）公共数据进行对比、分析两种亚型的疾病在生物学过程及信号通路上的相似性。 结果： 6例HAPH患者年龄（68.1±8.3）岁，男性2例（2/6）；4例对照组受试者年龄（62.3±10.9）岁，男性2例（2/4）。HAPH组三尖瓣反流速度、三尖瓣压力梯度及肺动脉收缩压较对照组明显升高（P<0.05）。RNA测序结果示，与对照组相比，HAPH组外周血单个核细胞中显著高表达基因有174个，显著低表达基因有169个，这些差异表达的基因与220个生物学过程、52个分子功能和23个细胞组分相关。筛选到HAPH与IPAH共同的生物学过程21个、信号通路2条，多数与炎症和免疫反应相关。经转录因子基因表达调控网络构建筛选到ZNF384、SP1、STAT3等与HAPH高相关性的转录因子。药物相似性分析筛选出了曲古菌素A和伏立诺他两种潜在的治疗HAPH的药物。 结论： HAPH患者与正常人群外周血单核细胞基因表达上存在较大的差异，炎症和免疫功能紊乱是主要致病因素。曲古菌素A和伏立诺他是治疗HAPH的潜在药物。.