Identification of Hub Genes and MicroRNAs Associated With Idiopathic Pulmonary Arterial Hypertension by Integrated Bioinformatics Analyses.

Xue Qiu,Yanbing Chen,Jinyan Lin,Jing Zheng,Guoqun Liu,Bixiao Liang

doi:10.3389/fgene.2021.636934

Abstract

ObjectiveThe aim of this study is the identification of hub genes associated with idiopathic pulmonary arterial hypertension (IPAH).Materials and MethodsGSE15197 gene expression data was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by screening IPAH patients and controls. The 5,000 genes with the greatest variances were analyzed using a weighted gene co-expression network analysis (WGCNA). Modules with the strongest correlation with IPAH were chosen, followed by a functional enrichment analysis. Protein–protein interaction (PPI) networks were constructed to identify hub gene candidates using calculated degrees. Real hub genes were found from the overlap of DEGs and candidate hub genes. microRNAs (miRNAs) targeting real hub genes were found by screening miRNet 2.0. The most important IPAH miRNAs were identified.ResultsThere were 4,395 DEGs identified. WGCNA indicated that green and brown modules associated most strongly with IPAH. Functional enrichment analysis showed that green and brown module genes were mainly involved in protein digestion and absorption and proteoglycans in cancer, respectively. The top ten candidate hub genes in green and brown modules were identified, respectively. After overlapping with DEGs, 11 real hub genes were identified: EP300, MMP2, CDH2, CDK2, GNG10, ALB, SMC2, DHX15, CUL3, BTBD1, and LTN1. These genes were expressed with significant differences in IPAH versus controls, indicating a high diagnostic ability. The miRNA–gene network showed that hsa-mir-1-3p could associate with IPAH.ConclusionEP300, MMP2, CDH2, CDK2, GNG10, ALB, SMC2, DHX15, CUL3, BTBD1, and LTN1 may play essential roles in IPAH. Predicted miRNA hsa-mir-1-3p could regulate gene expression in IPAH. Such hub genes may contribute to the pathology and progression in IPAH, providing potential diagnostic and therapeutic opportunities for IPAH patients.

Highlights

Idiopathic pulmonary arterial hypertension (IPAH) is a pulmonary proliferative vasculopathy (Gallo de Moraes et al, 2016)
The top 20 differentially expressed genes (DEGs) are listed in Supplementary Table 2
From the module–trait relationships analysis (Figure 2D), we found that the green (r = 0.74, p < 0.001), blue (r = 0.59, p < 0.001), black (r = 0.58, p < 0.001), and brown modules (r = −0.60, p < 0.001) were strongly related to the IPAH disease status

Summary

Introduction

Idiopathic pulmonary arterial hypertension (IPAH) is a pulmonary proliferative vasculopathy (Gallo de Moraes et al, 2016). Pathological changes including plexiform lesions, cellular proliferation, fibrosis, in situ thrombosis of the small pulmonary arteries and arterioles, and angiogenic dysfunction, leading to increased pulmonary vascular resistance, result in IPAH (Barnes et al, 2019). In the last 20 years, new therapies have been developed, improving hemodynamics and long-term prognosis (Wang Y. et al, 2019). For those not sensitive to therapy, surgery such as atrial septostomy and lung transplantation are options, the prognosis is poor (Pahal and Sharma, 2020)

Methods

Results

Discussion

Conclusion