College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
Beijing Genomeics Institute At Shenzhen, BGI-Shenzhen, Shenzhen, China.
Front Cell Infect Microbiol. 2022 May 27;12:888582. doi: 10.3389/fcimb.2022.888582. eCollection 2022.
Host genetic factors have been shown to play an important role in SARS-CoV-2 infection and the course of Covid-19 disease. The genetic contributions of common variants influencing Covid-19 susceptibility and severity have been extensively studied in diverse populations. However, the studies of rare genetic defects arising from inborn errors of immunity (IEI) are relatively few, especially in the Chinese population. To fill this gap, we used a deeply sequenced dataset of nearly 500 patients, all of Chinese descent, to investigate putative functional rare variants. Specifically, we annotated rare variants in our call set and selected likely deleterious missense (LDM) and high-confidence predicted loss-of-function (HC-pLoF) variants. Further, we analyzed LDM and HC-pLoF variants between and Covid-19 patients by (a) performing gene- and pathway-level association analyses, (b) testing the number of mutations in previously reported genes mapped from LDM and HC-pLoF variants, and (c) uncovering candidate genes protein-protein interaction (PPI) network analysis of Covid-19-related genes and genes defined from LDM and HC-pLoF variants. From our analyses, we found that (a) pathways Tuberculosis (hsa:05152), Primary Immunodeficiency (hsa:05340), and Influenza A (hsa:05164) showed significant enrichment in patients compared to the ones, (b) HC-pLoF mutations were enriched in Covid-19-related genes in patients, and (c) several candidate genes, such as , , , and , are uncovered by PPI network analysis and worth further investigation. These regions generally play an essential role in regulating antiviral innate immunity responses to foreign pathogens and in responding to many inflammatory diseases. We believe that our identified candidate genes/pathways can be potentially used as Covid-19 diagnostic markers and help distinguish patients at higher risk.
宿主遗传因素已被证明在 SARS-CoV-2 感染和 COVID-19 疾病过程中发挥重要作用。在不同人群中，广泛研究了影响 COVID-19 易感性和严重程度的常见变体的遗传贡献。然而，由于先天性免疫缺陷（IEI）引起的罕见遗传缺陷的研究相对较少，特别是在中国人群中。为了填补这一空白，我们使用了近 500 名患者的深度测序数据集，这些患者均为华裔，以研究可能具有功能的罕见变异。具体来说，我们对我们的调用集中的罕见变异进行注释，并选择可能有害的错义（LDM）和高置信度预测功能丧失（HC-pLoF）变异。此外，我们通过（a）进行基因和途径水平的关联分析，（b）测试从 LDM 和 HC-pLoF 变异映射的先前报道基因中的突变数量，以及（c）揭示候选基因 COVID-19 相关基因和从 LDM 和 HC-pLoF 变异定义的基因的蛋白质-蛋白质相互作用（PPI）网络分析，分析 COVID-19 患者和 患者之间的 LDM 和 HC-pLoF 变异。从我们的分析中，我们发现：（a）与 患者相比，途径结核病（hsa:05152）、原发性免疫缺陷（hsa:05340）和流感 A（hsa:05164）显著富集，（b）HC-pLoF 突变在 COVID-19 相关基因中富集，（c）通过 PPI 网络分析发现了几个候选基因，如 、 、 和 ，值得进一步研究。这些区域通常在调节抗病毒先天免疫对外来病原体的反应以及应对许多炎症性疾病方面发挥重要作用。我们相信，我们鉴定的候选基因/途径可潜在用作 COVID-19 诊断标志物，并有助于区分高危患者。
