Table1_Identification and validation of potential hypoxia-related genes associated with coronary artery disease.DOCX

Introduction: Coronary artery disease (CAD) is one of the most life-threatening cardiovascular emergencies with high mortality and morbidity. Increasing evidence has demonstrated that the degree of hypoxia is closely associated with the development and survival outcomes of CAD patients. However, the role of hypoxia in CAD has not been elucidated.
Methods: Based on the GSE113079 microarray dataset and the hypoxia-associated gene collection, differential analysis, machine learning, and validation of the screened hub genes were carried out.
Results: In this study, 54 differentially expressed hypoxia-related genes (DE-HRGs), and then 4 hub signature genes (ADM, PPFIA4, FAM162A, and TPBG) were identified based on microarray datasets GSE113079 which including of 93 CAD patients and 48 healthy controls and hypoxia-related gene set. Then, 4 hub genes were also validated in other three CAD related microarray datasets. Through GO and KEGG pathway enrichment analyses, we found three upregulated hub genes (ADM, PPFIA4, TPBG) were strongly correlated with differentially expressed metabolic genes and all the 4 hub genes were mainly enriched in many immune-related biological processes and pathways in CAD. Additionally, 10 immune cell types were found significantly different between the CAD and control groups, especially CD8 T cells, which were apparently essential in cardiovascular disease by immune cell infiltration analysis. Furthermore, we compared the expression of 4 hub genes in 15 cell subtypes in CAD coronary lesions and found that ADM, FAM162A and TPBG were all expressed at higher levels in endothelial cells by single-cell sequencing analysis.
Discussion: The study identified four hypoxia genes associated with coronary heart disease. The findings provide more insights into the hypoxia landscape and, potentially, the therapeutic targets of CAD.

Introduction: 冠状动脉疾病（Coronary artery disease, CAD）是致死率与致残率均居高不下的最具生命威胁的心血管急症之一。越来越多的研究证据表明，缺氧程度与CAD患者的病情进展及生存结局密切相关，但缺氧在CAD中所扮演的具体作用仍未阐明。
Methods: 本研究基于GSE113079微阵列数据集与缺氧相关基因集，开展了差异表达分析、机器学习分析，并对筛选得到的核心基因进行了验证。
Results: 本研究针对包含93名CAD患者与48名健康对照的GSE113079微阵列数据集及缺氧相关基因集进行分析，共筛选得到54个缺氧相关差异表达基因（DE-HRGs），并进一步识别出4个核心特征基因：ADM、PPFIA4、FAM162A与TPBG。随后，我们在另外3个CAD相关微阵列数据集内对这4个核心基因进行了验证。通过基因本体（Gene Ontology, GO）与京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）通路富集分析，我们发现3个上调核心基因（ADM、PPFIA4、TPBG）与差异表达代谢基因显著相关，且4个核心基因主要富集于CAD中多种免疫相关的生物学过程与通路。此外，通过免疫细胞浸润分析，我们发现CAD组与健康对照组间共有10种免疫细胞的浸润水平存在显著差异，其中CD8+ T细胞在心血管疾病中发挥着至关重要的作用。进一步，我们通过单细胞测序分析，对比了CAD冠脉病变组织内15种细胞亚型中4个核心基因的表达情况，发现ADM、FAM162A与TPBG在内皮细胞中均呈现高表达。
Discussion: 本研究明确了4个与冠心病相关的缺氧相关基因，研究结果为解析CAD的缺氧调控图谱提供了新的见解，同时也为该病潜在的治疗靶点开发提供了理论支撑。