Department of Neurosurgery, Xi'an Central Hospital, Xi'an Jiaotong University, No. 161, West 5th Road, Xincheng District, Xi'an, 710003, Shanxi, China.
Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Street, Changsha, 410008, Hunan, China.
Inflamm Res. 2024 Apr;73(4):619-640. doi: 10.1007/s00011-024-01857-w. Epub 2024 Mar 3.
Patients with coronavirus disease 2019 (COVID-19) were vulnerable to venous thromboembolism (VTE), which further increases the risk of unfavorable outcomes. However, neither genetic correlations nor shared genes underlying COVID-19 and VTE are well understood.
This study aimed to characterize genetic correlations and common pathogenic mechanisms between COVID-19 and VTE.
We used linkage disequilibrium score (LDSC) regression and Mendelian Randomization (MR) analysis to investigate the genetic associations and causal effects between COVID-19 and VTE, respectively. Then, the COVID-19 and VTE-related datasets were obtained from the Gene Expression Omnibus (GEO) database and analyzed by bioinformatics and systems biology approaches with R software, including weighted gene co-expression network analysis (WGCNA), enrichment analysis, and single-cell transcriptome sequencing analysis. The miRNA-genes and transcription factor (TF)-genes interaction networks were conducted by NetworkAnalyst. We performed the secondary analysis of the ATAC-seq and Chip-seq datasets to address the epigenetic-regulating relationship of the shared genes.
This study demonstrated positive correlations between VTE and COVID-19 by LDSC and bidirectional MR analysis. A total of 26 potential shared genes were discovered from the COVID-19 dataset (GSE196822) and the VTE dataset (GSE19151), with 19 genes showing positive associations and 7 genes exhibiting negative associations with these diseases. After incorporating two additional datasets, GSE164805 (COVID-19) and GSE48000 (VTE), two hub genes TP53I3 and SLPI were identified and showed up-regulation and diagnostic capabilities in both illnesses. Furthermore, this study illustrated the landscapes of immune processes in COVID-19 and VTE, revealing the downregulation in effector memory CD8+ T cells and activated B cells. The single-cell sequencing analysis suggested that the hub genes were predominantly expressed in the monocytes of COVID-19 patients at high levels. Additionally, we identified common regulators of hub genes, including five miRNAs (miR-1-3p, miR-203a-3p, miR-210-3p, miR-603, and miR-124-3p) and one transcription factor (RELA).
Collectively, our results highlighted the significant correlations between COVID-19 and VTE and pinpointed TP53I3 and SLPI as hub genes that potentially link the severity of both conditions. The hub genes and their common regulators might present an opportunity for the simultaneous treatment of these two diseases.
新冠肺炎（COVID-19）患者易发生静脉血栓栓塞症（VTE），这进一步增加了不良结局的风险。然而，COVID-19 和 VTE 的遗传相关性和共同基因尚不清楚。
本研究旨在描述 COVID-19 和 VTE 之间的遗传相关性和共同发病机制。
我们分别使用连锁不平衡评分（LDSC）回归和孟德尔随机化（MR）分析来研究 COVID-19 和 VTE 之间的遗传关联和因果效应。然后，从基因表达综合数据库（GEO）数据库中获得 COVID-19 和 VTE 相关数据集，并使用 R 软件的生物信息学和系统生物学方法进行分析，包括加权基因共表达网络分析（WGCNA）、富集分析和单细胞转录组测序分析。使用 NetworkAnalyst 进行 miRNA-基因和转录因子（TF）-基因相互作用网络分析。我们对 ATAC-seq 和 Chip-seq 数据集进行了二次分析，以解决共享基因的表观遗传调控关系。
通过 LDSC 和双向 MR 分析，本研究证明了 VTE 和 COVID-19 之间存在正相关。从 COVID-19 数据集（GSE196822）和 VTE 数据集（GSE19151）中发现了 26 个潜在的共享基因，其中 19 个基因与这些疾病呈正相关，7 个基因呈负相关。在纳入另外两个数据集 GSE164805（COVID-19）和 GSE48000（VTE）后，鉴定出两个枢纽基因 TP53I3 和 SLPI，并在两种疾病中表现出上调和诊断能力。此外，本研究描绘了 COVID-19 和 VTE 中免疫过程的图谱，揭示了效应记忆 CD8+T 细胞和激活 B 细胞的下调。单细胞测序分析表明，这些枢纽基因主要在 COVID-19 患者的单核细胞中高水平表达。此外，我们还确定了枢纽基因的共同调控因子，包括 5 个 miRNA（miR-1-3p、miR-203a-3p、miR-210-3p、miR-603 和 miR-124-3p）和 1 个转录因子（RELA）。
综上所述，我们的研究结果突出了 COVID-19 和 VTE 之间的显著相关性，并确定了 TP53I3 和 SLPI 作为枢纽基因，可能将两种疾病的严重程度联系起来。枢纽基因及其共同调控因子可能为同时治疗这两种疾病提供机会。
