A common TMPRSS2 variant has a protective effect against severe COVID-19.
A common TMPRSS2 variant has a protective effect against severe COVID-19.
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DOI：
10.1016/j.retram.2022.103333
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发表时间：
2022-05
影响因子：
4.1
通讯作者：
Sternberg MJ
中科院分区：
文献类型：
--
作者：
David A;Parkinson N;Peacock TP;Pairo-Castineira E;Khanna T;Cobat A;Tenesa A;Sancho-Shimizu V;GenOMICC Consortium;ISARIC4C Investigators;Casanova JL;Abel L;Barclay WS;Baillie JK;Sternberg MJ
人蛋白跨膜型丝氨酸蛋白酶2(TMPRSS2)在SARS-CoV-2感染中起关键作用，因为它需要激活病毒的刺突蛋白，促进进入靶细胞。我们推测，影响TMPRSS2蛋白结构和功能的自然产生的TMPRSS2人类遗传变异可能调节SARS-CoV-2感染的严重程度。我们重点研究了唯一一个常见的预测具有破坏性的TMPRSS2非同义变体(rs12329760C>；T，p.V160M)，它的次要等位基因频率从德语犹太人的0.14到东亚人的0.38不等。我们分析了来自208个英国重症监护病房的2,244名患有新冠肺炎的危重患者的rs12329760与新冠肺炎严重程度的相关性，这些患者来自英国重症监护病房，作为GEOMICC(重症监护死亡率遗传学)研究的一部分。Logistic回归分析调整了性别、年龄和剥夺指数。体外实验中，将ACE2与TMPRSS2野生型或突变型(TMPRSS2V160M)共转染HEK293细胞。用SARS-CoV-2假病毒进入实验研究TMPRSS2V160M促进病毒进入的能力。我们发现rs12329760的T等位基因与发生严重新冠肺炎的可能性降低相关(OR 0.87，95%CI：0.79~0.97，P=0.0.01)。与一般人群相比，纯合子个体的这种关联性更强(OR0.65，95%CI：0.50-0.84，p=111.30×10.10−3)。我们在体外证明，这种导致氨基酸取代缬氨酸为蛋氨酸的变体，影响了TMPRSS2的催化活性，并且不能支持SARS-CoV-2刺激物进入细胞。TMPRSS2rs12329760是一种常见的变异，与严重新冠肺炎的风险显著降低相关。需要进一步的研究来评估TMPRSS2在不同年龄组中的表达。此外，我们的结果确定TMPRSS2是一个有希望的药物靶点，甲磺酸卡莫司坦，一种被批准用于治疗慢性胰腺炎和术后反流性食管炎的药物，在治疗新冠肺炎中有潜在的作用。需要临床试验来证实这一点。
The human protein transmembrane protease serine type 2 (TMPRSS2) plays a key role in SARS-CoV-2 infection, as it is required to activate the virus’ spike protein, facilitating entry into target cells. We hypothesized that naturally-occurring TMPRSS2 human genetic variants affecting the structure and function of the TMPRSS2 protein may modulate the severity of SARS-CoV-2 infection. We focused on the only common TMPRSS2 non-synonymous variant predicted to be damaging (rs12329760 C>T, p.V160M), which has a minor allele frequency ranging from 0.14 in Ashkenazi Jewish to 0.38 in East Asians. We analysed the association between the rs12329760 and COVID-19 severity in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units recruited as part of the GenOMICC (Genetics Of Mortality In Critical Care) study. Logistic regression analyses were adjusted for sex, age and deprivation index. For in vitro studies, HEK293 cells were co-transfected with ACE2 and either TMPRSS2 wild type or mutant (TMPRSS2V160M). A SARS-CoV-2 pseudovirus entry assay was used to investigate the ability of TMPRSS2V160M to promote viral entry. We show that the T allele of rs12329760 is associated with a reduced likelihood of developing severe COVID-19 (OR 0.87, 95%CI:0.79–0.97, p = 0.01). This association was stronger in homozygous individuals when compared to the general population (OR 0.65, 95%CI:0.50–0.84, p = 1.3 × 10−3). We demonstrate in vitro that this variant, which causes the amino acid substitution valine to methionine, affects the catalytic activity of TMPRSS2 and is less able to support SARS-CoV-2 spike-mediated entry into cells. TMPRSS2 rs12329760 is a common variant associated with a significantly decreased risk of severe COVID-19. Further studies are needed to assess the expression of TMPRSS2 across different age groups. Moreover, our results identify TMPRSS2 as a promising drug target, with a potential role for camostat mesilate, a drug approved for the treatment of chronic pancreatitis and postoperative reflux esophagitis, in the treatment of COVID-19. Clinical trials are needed to confirm this.
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影响因子：
5.4
作者：
Heurich, Adeline;Hofmann-Winkler, Heike;Poehlmann, Stefan
通讯作者：
Poehlmann, Stefan
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
危及生命的Covid-19患者中针对I型IFN的自身抗体。
DOI：
10.1126/science.abd4585
发表时间：
2020-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bastard P;Rosen LB;Zhang Q;Michailidis E;Hoffmann HH;Zhang Y;Dorgham K;Philippot Q;Rosain J;Béziat V;Manry J;Shaw E;Haljasmägi L;Peterson P;Lorenzo L;Bizien L;Trouillet-Assant S;Dobbs K;de Jesus AA;Belot A;Kallaste A;Catherinot E;Tandjaoui-Lambiotte Y;Le Pen J;Kerner G;Bigio B;Seeleuthner Y;Yang R;Bolze A;Spaan AN;Delmonte OM;Abers MS;Aiuti A;Casari G;Lampasona V;Piemonti L;Ciceri F;Bilguvar K;Lifton RP;Vasse M;Smadja DM;Migaud M;Hadjadj J;Terrier B;Duffy D;Quintana-Murci L;van de Beek D;Roussel L;Vinh DC;Tangye SG;Haerynck F;Dalmau D;Martinez-Picado J;Brodin P;Nussenzweig MC;Boisson-Dupuis S;Rodríguez-Gallego C;Vogt G;Mogensen TH;Oler AJ;Gu J;Burbelo PD;Cohen JI;Biondi A;Bettini LR;D'Angio M;Bonfanti P;Rossignol P;Mayaux J;Rieux-Laucat F;Husebye ES;Fusco F;Ursini MV;Imberti L;Sottini A;Paghera S;Quiros-Roldan E;Rossi C;Castagnoli R;Montagna D;Licari A;Marseglia GL;Duval X;Ghosn J;HGID Lab;NIAID-USUHS Immune Response to COVID Group;COVID Clinicians;COVID-STORM Clinicians;Imagine COVID Group;French COVID Cohort Study Group;Milieu Intérieur Consortium;CoV-Contact Cohort;Amsterdam UMC Covid-19 Biobank;COVID Human Genetic Effort;Tsang JS;Goldbach-Mansky R;Kisand K;Lionakis MS;Puel A;Zhang SY;Holland SM;Gorochov G;Jouanguy E;Rice CM;Cobat A;Notarangelo LD;Abel L;Su HC;Casanova JL
通讯作者：
Casanova JL
DOI：
10.1534/g3.118.200144
发表时间：
2018-07-02
期刊：
G3 (Bethesda, Md.)
影响因子：
--
作者：
Edie S;Zaghloul NA;Leitch CC;Klinedinst DK;Lebron J;Thole JF;McCallion AS;Katsanis N;Reeves RH
通讯作者：
Reeves RH
影响因子：
5.4
作者：
Glowacka, Ilona;Bertram, Stephanie;Poehlmann, Stefan
通讯作者：
Poehlmann, Stefan