Common variants at 21q22.3 locus influenceMX1gene expression and susceptibility to severe COVID-19

Abstract

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≤1×10−5) 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.

SARS-CoV-2 genomic surveillance identifies naturally occurring truncation of ORF7a that limits immune suppression

“…One of these differentially expressed ISGs (IFITM3) restricts SARS-CoV-2 entry (Shi et al, 2021;Zang et al, 2020). Additionally, polymorphisms in IFITM3, MX1, and TLR7 are linked to the severity of COVID-19 (Andolfo et al, 2020;Zhang et al, 2020a;Pati et al, 2021). Upregulation of ISGs indicates that the ORF7a D115 virus is inept at antagonizing the IFN-I response to the infection, which is consistent with results from our ISRE reporter assay (Figure 2F).…”

SARS-CoV-2 genomic surveillance identifies naturally occurring truncations of ORF7a that limit immune suppression

“…One of these differentially expressed ISGs (IFITM3) restricts SARS-CoV-2 entry (Shi et al, 2020; Zang et al, 2020). Additionally, polymorphisms in IFITM3, MX1 and TLR7 are linked to the severity of COVID-19 (Andolfo et al, 2020; Jin, R. et al, 2020; Pati et al, 2021). This upregulation of ISGs indicates that the ORF7a Δ115 mutation limits viral suppression of the IFN-I response, which is consistent with previous work suggesting that ORF7a prevents transcriptional activation by STAT1/STAT2 complex (Xia et al, 2020).…”

Regulatory Noncoding and Predicted Pathogenic Coding Variants of CCR5 Predispose to Severe COVID-19

“…The clinical manifestations of COVID-19 are very heterogeneous; indeed, they can range from completely asymptomatic subjects up to patients who are hospitalized and undergo mechanical ventilation [1]. Numerous studies have focused on discovering the causes of this spectrum of phenotypes and on the evaluation of the presence of genetic differences in the predisposition to this pathology [24][25][26].…”