Abstract
BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease that can affect multiple systems. Pulmonary arterial hypertension (PAH) has a close linkage with SLE. However, the inter-relational mechanisms between them are still unclear. This article aimed to explore the shared gene signatures and potential molecular mechanisms in SLE and PAH.MethodsThe microarray data of SLE and PAH in the Gene Expression Omnibus (GEO) database were downloaded. The Weighted Gene Co-Expression Network Analysis (WGCNA) was used to identify the co-expression modules related to SLE and PAH. The shared genes existing in the SLE and PAH were performed an enrichment analysis by ClueGO software, and their unique genes were also performed with biological processes analyses using the DAVID website. The results were validated in another cohort by differential gene analysis. Moreover, the common microRNAs (miRNAs) in SLE and PAH were obtained from the Human microRNA Disease Database (HMDD) and the target genes of whom were predicted through the miRTarbase. Finally, we constructed the common miRNAs–mRNAs network with the overlapped genes in target and shared genes. ResultsUsing WGCNA, four modules and one module were identified as the significant modules with SLE and PAH, respectively. A ClueGO enrichment analysis of shared genes reported that highly activated type I IFN response was a common feature in the pathophysiology of SLE and PAH. The results of differential analysis in another cohort were extremely similar to them. We also proposed a disease road model for the possible mechanism of PAH secondary to SLE according to the shared and unique gene signatures in SLE and PAH. The miRNA–mRNA network showed that hsa-miR-146a might regulate the shared IFN-induced genes, which might play an important role in PAH secondary to SLE.ConclusionOur work firstly revealed the high IFN response in SLE patients might be a crucial susceptible factor for PAH and identified novel gene candidates that could be used as biomarkers or potential therapeutic targets.
Highlights
Pulmonary arterial hypertension (PAH) is a rare and severe cardiopulmonary disease, which is caused by cellular proliferation and fibrosis of pulmonary arterioles and arteries, leading to a progressive rise of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP), eventually resulting in right heart failure and death [1]
PAH could be classified as idiopathic PAH (IPAH) and disease-associated PAH (APAH), the latter included the congenital heart diseasepulmonary artery hypertension (CHD-PAH) and connective tissue disease-pulmonary artery hypertension (CTD-PAH) [2]
A heat map was mapped about module–trait relationships according to the Spearman correlation coefficient to evaluate the association between each module and the disease (Figures 1A, B)
Summary
Pulmonary arterial hypertension (PAH) is a rare and severe cardiopulmonary disease, which is caused by cellular proliferation and fibrosis of pulmonary arterioles and arteries, leading to a progressive rise of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP), eventually resulting in right heart failure and death [1]. There must be some predisposing factors in SLE patients, which make them more prone to PAH It is well-known that SLE is a chronic autoimmune inflammatory disease characterized by the formation of circulating autoantibody [5]. Some studies have been demonstrated that some autoantibodies in SLE patients are highly related to PAH, such as anti-dsDNA antibody, anti-RNP antibody and antiphospholipid antibody [6, 7]. These studies were mainly from serological perspectives, and fail to reveal the mechanism of PAH secondary to SLE at the genetic level.
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