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

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.

Stress Reactivity, Susceptibility to Hypertension, and Differential Expression of Genes in Hypertensive Compared to Normotensive Patients

“…Using the PubMed database [ 69 ], we collected all the DEGs (of hypertensive compared with normotensive patients) that we could find ( Table 5 ). The total number of hypertension-related human DEGs found was 7865, as cited in the rightmost column of Table 5 [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ].…”

“…In this work, we analyzed all the publicly available independent experimental RNA-Seq datasets—on transcriptomes from the tissues of hypertensive versus normotensive patients [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ], hypertensive versus normotensive animals [ 7 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ], and domestic versus wild animals [ 72 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 ].…”

“…In this work, we analyzed all the publicly available independent experimental RNA-Seq datasets-on transcriptomes from the tissues of hypertensive versus normotensive patients [26][27][28][29][30][31][32][33][34][35][36][37][38][39], hypertensive versus normotensive animals [7,[40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57], and domestic versus wild animals [72,[176][177][178][179][180][181][182][183][184][185][186][187][188][189][190][191][192][193].…”

“…Parents of half of the hypertensive patients had hypertension, but all the known (>60) hypertension-related whole-genome human loci explained only 3% of this heritability of hypertension [ 25 ]. Maybe this is why mainstream transcriptome-profiling studies on hypertensive versus normotensive patients [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ] and animals [ 7 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ] are focused on the differentially expressed genes (DEGs) that are specific to gender, age, and the stage of hypertension development. This is needed in predictive preventive personalized participatory (4P) medicine [ 58 ] to estimate where, how, why, and when hypertension might occur in a given patient depending on his/her genetic background.…”

The Identification and Verification of Hub Genes Associated with Pulmonary Arterial Hypertension Using Weighted Gene Co-Expression Network Analysis

“…Dong H et al identi ed CSF3R, NT5E, ANGPT2, FGF7 and CXCL9 as candidate biomarkers of PAH, and ruxolitinib might exert promising therapeutic action for PAH[28]. Qiu X et al performed a WGCNA on GSE15197 and found 11 real hub genes, including EP300, MMP2, CDH2, CDK2, GNG10, ALB, SMC2, DHX15, CUL3, BTBD1, and LTN1, were over-expressed in IPAH[29]. Contrastly, Liu J et al suggested that 10 hub genes were determined via Cytohubba and a crucially ceRNA network was identi ed, including 14 LncRNAs, 2 miRNAs, and 3 mRNAs[30].…”