The COVID-19 disease, caused by the SARS-Cov-2, presents a heterogeneous clinical spectrum. The risk factors do not fully explain the wide spectrum of disease manifestations, so it is possible that genetic factors could account for novel insights into its pathogenesis. In our previous study, we hypothesized that common variants on chromosome 21, near TMPRSS2 and MX1 genes, may be genetic risk factors associated to the different clinical manifestations of COVID-19. Here, we performed an in-depth genetic analysis of chromosome 21 exploiting the genome-wide association study data including 6,406 individuals hospitalized for COVID-19 and 902,088 controls with European genetic ancestry from COVID-19 Host Genetics Initiative. We found that five single nucleotide polymorphisms (SNPs) within TMPRSS2 and near MX1 gene show suggestive associations (P≤1x10-5) with severe COVID-19. All five SNPs replicated the association in two independent cohorts of Asian subjects while two and one out of the 5 SNPs replicated in African and Italian populations, respectively (P≤0.05). The minor alleles of these five SNPs correlated with a reduced risk of developing severe COVID-19 and increased level of MX1 expression in blood. Our findings provide further evidence that host genetic factors can contribute to determine the different clinical presentations of COVID-19 and that MX1, an antiviral effector of type I and III interferon pathway, may be a potential therapeutic target.

中文翻译：

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21q22.3基因座的常见变异影响MX1基因表达和对严重COVID-19的敏感性

由SARS-Cov-2引起的COVID-19疾病表现出不同的临床范围。危险因素不能完全解释广泛的疾病表现，因此遗传因素有可能解释其发病机理的新颖见解。在我们以前的研究中，我们假设TMPRSS2和MX1基因附近的21号染色体上的常见变异可能是与COVID-19的不同临床表现相关的遗传危险因素。在这里，我们利用全基因组关联研究数据对21号染色体进行了深入的遗传分析，其中包括6,406名因COVID-19住院的患者和902,088名来自COVID-19 Host Genetics Initiative的欧洲遗传血统的对照。我们发现TMPRSS2内和MX1基因附近的五个单核苷酸多态性（SNP）与严重的COVID-19表现出暗示性关联（P≤1x10-5）。所有五个SNP在亚洲受试者的两个独立队列中均重复了该关联，而在非洲和意大利人群中分别复制了5个SNP中的两个和五个（P≤0.05）。这五个SNP的次要等位基因与发生严重COVID-19的风险降低以及血液中MX1表达水平升高相关。我们的发现提供了进一步的证据，表明宿主遗传因素可以决定COVID-19的不同临床表现，而MX1（I型和III型干扰素途径的抗病毒效应物）可能是潜在的治疗靶标。所有五个SNP在亚洲受试者的两个独立队列中均重复了该关联，而在非洲和意大利人群中分别复制了5个SNP中的两个和五个（P≤0.05）。这五个SNP的次要等位基因与发生严重COVID-19的风险降低以及血液中MX1表达水平升高相关。我们的发现提供了进一步的证据，表明宿主遗传因素可以决定COVID-19的不同临床表现，而MX1（I型和III型干扰素途径的抗病毒效应物）可能是潜在的治疗靶标。所有五个SNP在亚洲受试者的两个独立队列中均重复了该关联，而在非洲和意大利人群中分别复制了5个SNP中的两个和五个（P≤0.05）。这五个SNP的次要等位基因与发生严重COVID-19的风险降低以及血液中MX1表达水平升高相关。我们的发现提供了进一步的证据，表明宿主遗传因素可以决定COVID-19的不同临床表现，而MX1（I型和III型干扰素途径的抗病毒效应物）可能是潜在的治疗靶标。