Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan.
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
Nature. 2022 Sep;609(7928):754-760. doi: 10.1038/s41586-022-05163-5. Epub 2022 Aug 8.
Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
确定导致严重 COVID-19 的宿主遗传因素是一个新兴挑战。在这里，我们进行了一项全基因组关联研究（GWAS），涉及在大流行初期收集的日本个体队列中的 2393 例 COVID-19 病例，共有 3289 名未受影响的对照。我们在 5 号染色体上发现了一个位于 5q35 （rs60200309-A）的变体，该变体靠近细胞分裂器 2 基因（DOCK2），与 65 岁以下患者的严重 COVID-19 相关。该风险等位基因在东亚人群中普遍存在，但在欧洲人中罕见，突显了全基因组关联研究在非欧洲人群中的价值。对 473 个外周血样本的 RNA-seq 分析鉴定出与年轻患者中该风险等位基因相关的 DOCK2 表达降低。DOCK2 在严重 COVID-19 患者中的表达受到抑制。单细胞 RNA-seq 分析（n=61 人）鉴定出非经典单核细胞中 DOCK2 的细胞类型特异性下调，以及风险等位基因对 DOCK2 表达的 COVID-19 特异性降低效应。严重 COVID-19 肺炎患者肺标本的免疫组织化学显示 DOCK2 表达受到抑制。此外，用 CPYPP 抑制 DOCK2 功能会增加 SARS-CoV-2 感染叙利亚仓鼠模型中肺炎的严重程度，其特征为体重减轻、肺水肿、病毒载量增加、巨噬细胞募集受损和 I 型干扰素反应失调。我们得出结论，DOCK2 在宿主对 SARS-CoV-2 感染的免疫反应和严重 COVID-19 的发展中具有重要作用，可进一步作为潜在的生物标志物和/或治疗靶点进行探索。
