Common Variants at 21q22.3 Locus Influence MX1 Gene Expression and Susceptibility to Severe COVID-19

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 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 with 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 the 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 the five SNPs correlated with a reduced risk of developing severe COVID-19 and an increased level of MX1 expression in blood. One (rs12329760, V197M) of these SNPs resided in the exon 6 of TMPRSS2 and was also predicted to alter the protein conformation.Our findings provide further evidence that host genetic factors can contribute to determining the different clinical presentations of COVID-19 and that MX1, an antiviral effector of type I and III interferon pathway, could be a potential therapeutic target.Funding: This study was supported by the project "CEINGE TASK-FORCE COVID19", codeD64I200003800 by Regione Campania for the fight against Covid-19 (DGR n. 140 del 17 Marzo 2020).Conflict of Interest: Nothing to disclose.