Laboratory of Genomic Medicine, Center of Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil.
Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
Biochem Genet. 2024 Apr;62(2):892-914. doi: 10.1007/s10528-023-10453-2. Epub 2023 Jul 24.
Severe COVID-19 is a systemic disorder involving excessive inflammatory response, metabolic dysfunction, multi-organ damage, and several clinical features. Here, we performed a transcriptome meta-analysis investigating genes and molecular mechanisms related to COVID-19 severity and outcomes. First, transcriptomic data of cellular models of SARS-CoV-2 infection were compiled to understand the first response to the infection. Then, transcriptomic data from lung autopsies of patients deceased due to COVID-19 were compiled to analyze altered genes of damaged lung tissue. These analyses were followed by functional enrichment analyses and gene-phenotype association. A biological network was constructed using the disturbed genes in the lung autopsy meta-analysis. Central genes were defined considering closeness and betweenness centrality degrees. A sub-network phenotype-gene interaction analysis was performed. The meta-analysis of cellular models found genes mainly associated with cytokine signaling and other pathogen response pathways. The meta-analysis of lung autopsy tissue found genes associated with coagulopathy, lung fibrosis, multi-organ damage, and long COVID-19. Only genes DNAH9 and FAM216B were found perturbed in both meta-analyses. BLNK, FABP4, GRIA1, ATF3, TREM2, TPPP, TPPP3, FOS, ALB, JUNB, LMNA, ADRB2, PPARG, TNNC1, and EGR1 were identified as central elements among perturbed genes in lung autopsy and were found associated with several clinical features of severe COVID-19. Central elements were suggested as interesting targets to investigate the relation with features of COVID-19 severity, such as coagulopathy, lung fibrosis, and organ damage.
严重的 COVID-19 是一种全身性疾病，涉及过度的炎症反应、代谢功能障碍、多器官损伤和多种临床特征。在这里，我们进行了转录组元分析，以研究与 COVID-19 严重程度和结果相关的基因和分子机制。首先，我们编译了 SARS-CoV-2 感染细胞模型的转录组数据，以了解对感染的第一反应。然后，我们编译了因 COVID-19 而死亡的患者肺活检的转录组数据，以分析受损肺组织的改变基因。这些分析之后是功能富集分析和基因-表型关联。使用肺活检元分析中受干扰的基因构建了一个生物网络。中央基因是根据接近度和中间中心度来定义的。进行了子网络表型-基因相互作用分析。细胞模型的元分析发现，基因主要与细胞因子信号和其他病原体反应途径相关。肺活检组织的元分析发现与凝血功能障碍、肺纤维化、多器官损伤和长 COVID-19 相关的基因。只有基因 DNAH9 和 FAM216B 在这两个元分析中都被发现受到干扰。BLNK、FABP4、GRIA1、ATF3、TREM2、TPPP、TPPP3、FOS、ALB、JUNB、LMNA、ADRB2、PPARG、TNNC1 和 EGR1 被确定为肺活检中受干扰基因的核心元素，与严重 COVID-19 的多种临床特征相关。中央元素被认为是研究与 COVID-19 严重程度相关的特征（如凝血功能障碍、肺纤维化和器官损伤）的有趣靶点。
