Association of CXCR6 with COVID-19 severity: delineating the host genetic factors in transcriptomic regulation.
Association of CXCR6 with COVID-19 severity: delineating the host genetic factors in transcriptomic regulation.
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CXCR 6与COVID-19严重程度的关联：描述转录组调控中的宿主遗传因素。
DOI：
10.1007/s00439-021-02305-z
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发表时间：
2021-09
期刊：
影响因子：
5.3
通讯作者：
Zhao Z
中科院分区：
文献类型：
--
作者：
Dai Y;Wang J;Jeong HH;Chen W;Jia P;Zhao Z
2019年冠状病毒病（COVID-19）是一种主要影响宿主呼吸系统的传染病，约80%为无症状或轻度病例，约5%为重度病例。最近的全基因组关联研究（GWAS）已经确定了与严重COVID-19症状相关的几个遗传位点。描述遗传变异和基因对于更好地理解其生物学机制非常重要。我们实施了综合方法，包括全转录组关联研究（TWAS），共定位分析和功能元件预测分析，使用两个独立的GWAS数据集在肺和免疫细胞中解释遗传风险。为了了解背景特异性分子改变，我们进一步对来自中度和重度COVID-19患者的支气管肺泡灌洗液（BALF）数据集进行了基于深度学习的单细胞转录组学分析。我们发现并复制了CXCR 6和CCR 9基因的遗传调控表达。这两个基因分别对肺有保护作用，对全血有风险作用。GWAS和顺式表达数量性状基因座的共定位分析突出了对肺和免疫细胞中CXCR 6表达的调节作用。在肺驻留记忆CD 8 + T（TRM）细胞中，我们发现重度患者的CD 8 + T细胞比例比中度患者低2.24倍，CXCR 6的表达也较中度患者低。促炎性转录程序在从中度到重度患者的TRM细胞轨迹中突出显示。来自3p21.31基因座的CXCR 6与严重COVID-19相关。CXCR 6倾向于在重症患者的肺TRM细胞中具有较低的表达，这与来自TWAS分析的CXCR 6的保护作用一致。在线版本包含补充材料，可通过10.1007/s 00439 -021-02305-z获得。
The coronavirus disease 2019 (COVID-19) is an infectious disease that mainly affects the host respiratory system with ~ 80% asymptomatic or mild cases and ~ 5% severe cases. Recent genome-wide association studies (GWAS) have identified several genetic loci associated with the severe COVID-19 symptoms. Delineating the genetic variants and genes is important for better understanding its biological mechanisms. We implemented integrative approaches, including transcriptome-wide association studies (TWAS), colocalization analysis, and functional element prediction analysis, to interpret the genetic risks using two independent GWAS datasets in lung and immune cells. To understand the context-specific molecular alteration, we further performed deep learning-based single-cell transcriptomic analyses on a bronchoalveolar lavage fluid (BALF) dataset from moderate and severe COVID-19 patients. We discovered and replicated the genetically regulated expression of CXCR6 and CCR9 genes. These two genes have a protective effect on lung, and a risk effect on whole blood, respectively. The colocalization analysis of GWAS and cis-expression quantitative trait loci highlighted the regulatory effect on CXCR6 expression in lung and immune cells. In the lung-resident memory CD8+ T (TRM) cells, we found a 2.24-fold decrease of cell proportion among CD8+ T cells and lower expression of CXCR6 in the severe patients than moderate patients. Pro-inflammatory transcriptional programs were highlighted in the TRM cellular trajectory from moderate to severe patients. CXCR6 from the 3p21.31 locus is associated with severe COVID-19. CXCR6 tends to have a lower expression in lung TRM cells of severe patients, which aligns with the protective effect of CXCR6 from TWAS analysis. The online version contains supplementary material available at 10.1007/s00439-021-02305-z.
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