Candidate Genes Identified in Systemic Sclerosis-Related Pulmonary Arterial Hypertension Were Associated with Immunity, Inflammation, and Cytokines

Abstract

Background. Pulmonary complications of systemic sclerosis (SSc), including pulmonary arterial hypertension (PAH), are the leading causes of patient death. However, the precise molecular mechanisms of its etiology are unclear. This study’s objective was to identify the candidate genes involved in the progression of SSc-PAH and investigate the genes' function. Methods. The gene expression profiles of GSE33463 were obtained from the Gene Expression Omnibus (GEO) database. A free-scale gene coexpression network was constructed using the weighted gene coexpression network analysis (WGCNA) to explore the association between gene sets and clinical features and identify candidate biomarkers. Then, gene ontology analysis was performed. A second dataset was used, GSE19617, to validate the hub genes. The verified hub genes’ potential function was further explored using gene set enrichment analysis (GSEA). Results. Through average link-level clustering, a total of seven modules were classified. A total of 938 hub genes were identified in the key module, and the key module’s function mainly enriched was related to chemokine activities. Subsequently, four candidate genes, BTG3, CCR2, RAB10, and TMEM60, were filtered. The expression levels of these four hub genes were consistent in the GSE19617 and GSE33463 datasets. We plotted the ROC curve of the hub genes (all $\text{AUC}>0.70$ ). Furthermore, the results of the GSEA for hub genes were correlated with complement and inflammatory responses. Conclusions. The hub genes (BTG3, CCR2, RAB10, and TMEM60) performed well in distinguishing the SSc-PAH patients from controls, and some biological functions, related to immunity, inflammation, and cytokines, might pave the way for follow-up studies on the diagnosis and treatment of SSc-PAH.