Common variants at 21q22.3 locus influence MX1 and TMPRSS2 gene expression and susceptibility to severe COVID-19

Abstract

The established risk factors of coronavirus disease 2019 (COVID-19) are advanced age, male sex and comorbidities, but they do not fully explain the wide spectrum of disease manifestations. Genetic factors implicated in the host antiviral response provide for novel insights into its pathogenesis. 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 within TMPRSS2 and near MX1 gene show associations with severe COVID-19. The minor alleles of the five SNPs correlated with a reduced risk of developing severe COVID-19 and high level of MX1 expression in blood. Our findings demonstrate that host genetic factors can influence the different clinical presentations of COVID-19 and that MX1 could be a potential therapeutic target.

Host genetic factors determining COVID-19 susceptibility and severity

“… Function Gene/Locus Variant Population description Study design Sample size Outcomes Refs. Cell entry related genes Cell entry ACE1 * I/D polymorphism Spanish Hospitalized patients vs. controls 204 hospitalized patients (67 severe) vs. 536 controls D/D genotype associated with COVID-19 [74] Cell entry ACE1 * I/D polymorphism Czech Recovered patients vs. controls 410 recovered patients (164 symptomatic vs. 2579 controls I/I genotype associated with COVID-19 [76] Protease/ Cell entry TMPRSS2; MX1 rs3787946, rs9983330; rs12329760, rs2298661, rs9985159 European Hospitalized patients vs. controls 6406 hospitalized vs. 902,088 controls Associated with hospitalization and increased MX1 expression in blood [86] Genes of the innate and adaptive immunity Innate TLR3, UNC93, TICAM, TBK1, IRF3, IRF7, IFNAR1, IFNAR2 Deleterious rare variants Multiple Critical COVID-19 vs. asymptomatic 659 critical vs. 534 mild/asymptomatic patients Associated with critical COVID-19 and low IFN1-levels [17] Innate TLR3, IRF7, IRF9, TICAM1/TRIF, UNC93, TRAF3, TBK1, IRF3, NEMO/IKBKG, IFNAR1, IFNAR2, STAT1, STAT2 Deleterious rare variants Multiple Severe COVID-19 vs. mild and vs. controls 1864 COVID-19 cases (713 with severe and 1151 with mild disease) and 15,033 controls No association with severe COVID-19 or SARS-CoV-2 infection. [111] Innate TLR7 Deleterious rare variants African and Dutch Genetic and immunological phenotype 2 brother pairs Associated with decreased IFN-γ production [109] Innate …”

“…This can occur either at the plasma membrane by use of TMPRSS2 or in the endosome by cathepsin L [85] . Variants of TMPRSS2 and the nearby MX1 (myxoma resistance 1) gene in the HGI hospitalization metanalysis of European COVID-19 patients were explored [86] . MX1 is an antiviral effector protein with a broad specificity, including RNA and DNA viruses.…”

An immunogenetic view of COVID-19

“…The MX1 , MX2 and TMPRSS2 (transmembrane protease serine 2, which is critical for SARS-CoV-2 host cell entry ( Hoffmann et al, 2020 ), are closely linked at the chromosomal region 21q22.3 and linkage disequilibrium in that region is strong (r 2 > 0.8) in non-African populations. The minor (less frequent) alleles of five SNPs correlated with high of MX1 expression in blood and a reduced risk of developing severe COVID-19 in Europeans ( Andolfo et al, 2021 ). Previously, polymorphisms in the MX1 promoter associated with increased transcription in vitro were associated with decreased susceptibility to SARS in the Chinese Hong Kong population ( Ching et al, 2010 ).…”

Host polymorphisms and COVID-19 infection

“…The minor allele of four of the top five SNPs might reduce the expression of TMPRSS2 in lung tissues. The rs12329760 SNP, in addition to its eQTL role, decreased the stability of the protein and ACE2 binding, which might impede viral entry [40] . In silico analysis showed the creation of a de novo pocket protein associated with this variant [41] .…”