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

•Genetic analysis was performed on 7,970 individuals hospitalized for COVID-19•Five SNPs within TMPRSS2/MX1 locus (chr.21) are associated with severe COVID-19•The minor alleles of the five correlated high level MX1 expression in blood•MX1 could be a potential therapeutic target patients COVID-19 The established risk factors coronavirus disease 2019 (COVID-19) advanced age, male sex, and comorbidities, but they do not fully explain wide spectrum manifestations. Genetic implicated host antiviral response provide novel insights into its pathogenesis.We an in-depth genetic chromosome 21 exploiting genome-wide association study data, including 6,406 902,088 controls European ancestry from Host Genetics Initiative. We found that single nucleotide polymorphisms TMPRSS2 near gene show associations COVID-19. (SNPs) reduced developing blood.Our findings demonstrate can influence different clinical presentations target. pathogenesis. blood. 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Qian al.Initial whole-genome contribution susceptibility.Cell Discov. 6: 83Crossref (98) Entry depends binding surface unit S1 spike (S) virus receptor. engages employs cellular S-protein priming (Hoffmann 2020bHoffmann Kleine-Weber H. Schroeder Kruger Herrler Erichsen Schiergens T.S. Wu N.H. Nitsche al.SARS-CoV-2 cell blocked clinically proven inhibitor.Cell. 181: 271-280.e8Abstract (10821) Matsuyama 2010Matsuyama Nagata Shirato Kawase Takeda Taguchi Efficient activation transmembrane TMPRSS2.J. Virol. 2010; 84: 12658-12664Crossref (506) Particularly, then followed TMPRSS2-mediated cleavage viral S-protein. This process, defined priming, involves S1/S2 S2 sites which essential fusion membrane before 2020Matsuyama Nao Saito Takayama Sekizuka Katoh Kato al.Enhanced isolation TMPRSS2-expressing cells.Proc. Natl. Acad. Sci. U S 117: 7001-7003Crossref (746) use other proteases cathepsin B/L absence receptors. However, lungs (the primary organ infection), cannot substitute activity latter indispensable observed SARS-CoV MERS-CoV 2020aHoffmann Pohlmann multibasic site human lung cells.Mol. Cell. 78: 779-784.e5Abstract (942) interferon-?/? inducible encodes guanosine triphosphate metabolizing (Ciancanelli 2016Ciancanelli M.J. Abel S.Y. Casanova J.L. influenza: mouse Mx1 IRF7.Curr. Immunol. 2016; 38: 109-120Crossref (81) this study, further hypothesis, exploited GWAS meta-analysis data Initiative (COVID-19 Initiative, 2020COVID-19 InitiativeThe initiative, global initiative elucidate role pandemic.Eur. Hum. 28: 715-718Crossref (343) using summary statistics where were significance (p ? 5 × 10?8). Using 908,494 subjects origins, showing suggestive disease. All replicated cohorts Asian subjects, whereas confirmed African one SNP cohort. Significant eQTLs signals To prove (21q22.3) affect onset, analyzed available dataset released includes (Table S1). region appears significantly (https://www.covid19hg.org/results/) also demonstrated recently published investigate whether exist 21, selected 74 p 1 10?5 them S2). most significant signal represented rs13050728 = 2.76 10?12, OR 0.83, Figure 1A) maps INFRA2 gene. 10?5) tagged rs111783124 2.39 10?6, 1.17, 1B) rs3787946 2.73 0.87, 1C), respectively. intronic closest (Figure 1C); herein, named “TMPRSS2/MX1”. An inspection 13 linkage disequilibrium (LD) lead (r2 > 0.8, Table 1) values 2.7 10?6 5.8 strong LD each (r2?0.90, 0.8 0.9 6 10?4 0.04 1). sought replicate 14 three GenOMMIC non-European ancestry. 11 east asian (EAS) population; top South (SAS) population, (AFR) By TaqMan assay, typed rs12329760 variant samples 226 S3) 1848 Southern Italy collected Institute. additional 1915 770 cases, sequencing, obtained Network Genomes (NIG) database (Daga 2021Daga Fallerini Baldassarri Fava Valentino Doddato Benetti Furini Giliberti Tita al.Employing systematic approach biobanking analyzing advancing research.Eur. : 1-15PubMed After combining cohorts, protective factor against aggressive form 2, ORallele 0.89, Pallele 0.07; ORdominant 0.57, 0.01; ORCCvsTT 0.01). case-control effect mainly due TT genotype.Table 1Associations prioritization scoresRS numberEAOAMAFr2ORP_EURORP_EASORP_SASORP_AFRaScores GWAVA predictor tool.Region scoreaScores tool.TSS scorebScores CADD tool.Predicted functionbScores tool.ScorecGWAVA scores ranked smallest largest summed.Combined scorers3787946CG0.231.000.872.73 10?60.630.0260.710.020.740.070.160.29INTRONIC26rs9983330GA0.230.910.883.12 10?60.540.0040.730.040.790.160.310.64REGULATORY426rs12329760TC0.240.900.883.13 10?60.640.0290.760.080.780.140.320.41MISSENSE723rs2298661AC0.230.990.884.51 10?60.630.0300.670.010.600.010.180.35INTRONIC29rs9985159TC0.230.980.885.80 10?60.610.0180.750.060.980.890.160.46INTRONIC215rs2298660TC0.200.820.880.001NANANANANANA0.120.28INTRONIC24rs7364088AG0.260.840.910.002NANANANANANA0.190.23INTRONIC26rs2298663TC0.250.871.080.0051.490.0521.120.400.940.660.260.37REGULATORY415rs2094881CT0.250.871.080.0051.470.0581.100.470.930.600.290.26REGULATORY413rs8131649TC0.250.850.920.0070.640.0350.900.461.010.930.260.35REGULATORY412rs8134203TC0.260.851.080.0071.490.0581.090.540.910.500.260.41REGULATORY417rs8134216TC0.260.851.080.0071.540.0381.110.430.910.490.280.4REGULATORY419rs2104810AG0.260.851.080.0081.540.0401.100.470.900.480.230.35REGULATORY411rs8131648CT0.260.851.070.036NANANANANANA0.330.42REGULATORY426In bold least cohort.EA: Effect Allele; OA: EUR: European; EAS: East Asian; SAS: AFR: African; ITA: Italian; MAF: frequency; OR: odds ratio.a Scores tool.b tool.c summed. Open table new tab 2Association populationGenotypeSI casesn 226SI controlsn 1848NIG 770NIG 1915All 996All 3763PSIOR (CI: 95%)PNIGOR 95%)PAllOR 95%)n%n%n%n%n%n%CC16472.6127468.953269.1128967.369669.9256368.1–––CT5725.249726.922028.655428.927727.8105127.90.470.89 (0.64–1.22)0.680.96 (0.79–1.15)0.710.97 (0.83–1.13)TT52.2774.2182.3723.8232.31494.00.140.50 (0.20–1.26)0.060.60 (0.35–1.02)0.010.57 (0.36–0.89)AlleleC38585.2304582.4128483.4313281.8166983.8617782.1–––T6714.865117.625616.669818.232316.2134917.90.140.81 (0.62–1.07)0.160.89 (0.76–1.04)0.070.89 (0.78–1.01)DominantCC/CT22197.8177195.875297.7184396.297397.7361496.0–––TT52.2774.2182.3723.8232.31494.00.150.52 (0.20–1.30)0.060.61 (0.36–1.03)0.010.57 (0.37–0.89)RecessiveCC15970.4127468.953269.1128967.369169.4256368.1–––CT/TT6227.457431.123830.962632.730030.1120031.90.260.84 (0.61–1.14)0.370.92 (0.76–1.10)0.280.92 (0.79–1.07)NIG, Genomes; OR, ratio; CI, confidence interval; SI, Italy.In highlighted statistically results. EA: ratio. NIG, Italy. tested if their proxy 0.8) over-represented active enhancers promoters types tissues HaploReg v4.1. These enriched regulatory regions several S4) best enrichment induced pluripotent stem cells thymus 2A). investigated predicted functional tools. SNPs, i.e. rs9983330 rs12329760, (combined score 26) 23) classified (p.Val197Met) localized exon pathogenic (PolyPhen-2 probably damaging SIFT deleterious). verified might cause alterations interrogating GTEx portal all locus. had eQTL exclusively tissue. higher compared major (Figures 2B S2A). Of note, except rs2298660, did have S5). rs2298660 1.79 2.8 alleles) interrogation another publicly (Westra 2013Westra H.J. Peters Esko Yaghootkar Schurmann Kettunen Christiansen M.W. Fairfax B.P. Schramm Powell J.E. al.Systematic identification trans putative drivers known associations.Nat. 2013; 45: 1238-1243Crossref (1187) highly expressed Scholar), nominally 0.05). four out lower 2C S2B). 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Pathog. 150: 104621Crossref (42) glycoprotein binds making it cell. serine allows membranes, resulting replication (Singh driving expression, mild-to-moderate elevated confer less individual favor better outcome Here, origins 21. (rs3787946, rs9983330, rs2298661, rs9985159) 21q22.3 particular, frequency recurrent when control individuals, suggesting progression Interestingly, origin, case series origin. As “proof concept”, detected (Hou 2020Hou Zhao Martin Kallianpur Chung M.K. Jehi Sharifi Erzurum Eng Cheng polymorphism analysis.BMC 18: 216Crossref (212) Vargas-Alarcon 2020Vargas-Alarcon Posadas-Sanchez Ramirez-Bello Variability related (ACE2, TMPRSS2, TMPRSS11A, ELANE, CTSL) studies.Life 260: 118313Crossref (33) It SNP, addition role, decreased stability protein, impede (Vishnubhotla 2020Vishnubhotla Vankadari Ketavarapu Amanchy Avanthi Bale Reddy D.N. Sasikala Structure complex.bioRxiv. Scholar); moreover, silico created de novo pocket (Paniri 2020Paniri Hosseini M.M. Akhavan-Niaki First comprehensive computational consequences populations.J. Biomol. Struct. Dyn. 1-18Crossref (53) confirm unfavorable Furthermore, molecular underlying predisposition ethnicit