Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Front Immunol. 2021 Jul 15;12:658341. doi: 10.3389/fimmu.2021.658341. eCollection 2021.
Systemic 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.
The 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.
Using 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.
Our 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.
系统性红斑狼疮（SLE）是一种可影响多个系统的自身免疫性疾病。肺动脉高压（PAH）与 SLE 密切相关。然而，它们之间的相互关系机制尚不清楚。本文旨在探讨 SLE 和 PAH 中的共享基因特征和潜在分子机制。
从基因表达综合数据库（GEO）下载 SLE 和 PAH 的微阵列数据。使用加权基因共表达网络分析（WGCNA）识别与 SLE 和 PAH 相关的共表达模块。使用 ClueGO 软件对 SLE 和 PAH 中存在的共享基因进行富集分析，并使用 DAVID 网站对其独特基因进行生物学过程分析。通过差异基因分析在另一个队列中验证结果。此外，从人类 microRNA 疾病数据库（HMDD）和 miRTarbase 获得 SLE 和 PAH 中的常见 microRNA（miRNA），并预测其靶基因。最后，我们用目标基因的重叠基因构建了 SLE 和 PAH 中共同的 miRNAs-mRNAs 网络。
使用 WGCNA，分别确定了与 SLE 和 PAH 相关的四个模块和一个模块。对共享基因的 ClueGO 富集分析表明，I 型干扰素反应的高度激活是 SLE 和 PAH 病理生理学的共同特征。另一个队列中的差异分析结果与它们非常相似。根据 SLE 和 PAH 中的共享和独特基因特征，我们还提出了一个可能的 PAH 继发于 SLE 的疾病路径模型。miRNA-mRNA 网络表明，hsa-miR-146a 可能调节共享的 IFN 诱导基因，这可能在 PAH 继发于 SLE 中发挥重要作用。
我们的工作首次揭示了 SLE 患者中高 IFN 反应可能是 PAH 的一个关键易感因素，并确定了新的基因候选物，这些候选物可作为生物标志物或潜在的治疗靶点。
