Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19.
Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19.
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DOI：
10.1038/s41591-021-01310-z
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发表时间：
2021-04
期刊：
影响因子：
82.9
通讯作者：
VA Million Veteran Program COVID-19 Science Initiative
中科院分区：
文献类型：
--
作者：
Gaziano L;Giambartolomei C;Pereira AC;Gaulton A;Posner DC;Swanson SA;Ho YL;Iyengar SK;Kosik NM;Vujkovic M;Gagnon DR;Bento AP;Barrio-Hernandez I;Rönnblom L;Hagberg N;Lundtoft C;Langenberg C;Pietzner M;Valentine D;Gustincich S;Tartaglia GG;Allara E;Surendran P;Burgess S;Zhao JH;Peters JE;Prins BP;Angelantonio ED;Devineni P;Shi Y;Lynch KE;DuVall SL;Garcon H;Thomann LO;Zhou JJ;Gorman BR;Huffman JE;O'Donnell CJ;Tsao PS;Beckham JC;Pyarajan S;Muralidhar S;Huang GD;Ramoni R;Beltrao P;Danesh J;Hung AM;Chang KM;Sun YV;Joseph J;Leach AR;Edwards TL;Cho K;Gaziano JM;Butterworth AS;Casas JP;VA Million Veteran Program COVID-19 Science Initiative
药物再利用提供了一种快速的方法来满足对治疗COVID-19的迫切需求。为了确定与COVID-19相关的治疗靶点，我们进行了孟德尔随机化（MR）分析，基于已批准药物靶向或处于药物开发临床阶段的1，263种可操作蛋白质的转录组学和蛋白质组学数据推导遗传工具。使用宿主遗传学倡议和百万退伍军人计划的汇总统计数据，我们研究了7，554名因COVID-19住院的患者和> 100万名对照。我们使用顺式eQTL遗传工具发现了三种蛋白质（ACE 2：P=1.6×10-6，IFNAR 2：P=9.8×10-11和IL-10 RB：P=2.3×10-14）的显著孟德尔随机化结果，这些结果也有强有力的证据表明与COVID-19住院共定位。为了解开IL 10 RB和IFNAR 2的共享eQTL信号，我们进行了全表型关联扫描和途径富集分析，这表明IFNAR 2更有可能在COVID-19住院中发挥作用。我们的研究结果优先考虑针对IFNAR 2和ACE 2的药物试验，以早期管理COVID-19。
Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization (MR) analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2: P=1.6×10-6, IFNAR2: P=9.8×10-11, and IL-10RB: P=2.3×10-14) using cis-eQTL genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared eQTL signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.
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影响因子：
3.7
作者：
Gold L;Ayers D;Bertino J;Bock C;Bock A;Brody EN;Carter J;Dalby AB;Eaton BE;Fitzwater T;Flather D;Forbes A;Foreman T;Fowler C;Gawande B;Goss M;Gunn M;Gupta S;Halladay D;Heil J;Heilig J;Hicke B;Husar G;Janjic N;Jarvis T;Jennings S;Katilius E;Keeney TR;Kim N;Koch TH;Kraemer S;Kroiss L;Le N;Levine D;Lindsey W;Lollo B;Mayfield W;Mehan M;Mehler R;Nelson SK;Nelson M;Nieuwlandt D;Nikrad M;Ochsner U;Ostroff RM;Otis M;Parker T;Pietrasiewicz S;Resnicow DI;Rohloff J;Sanders G;Sattin S;Schneider D;Singer B;Stanton M;Sterkel A;Stewart A;Stratford S;Vaught JD;Vrkljan M;Walker JJ;Watrobka M;Waugh S;Weiss A;Wilcox SK;Wolfson A;Wolk SK;Zhang C;Zichi D
通讯作者：
Zichi D
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
影响因子：
17.1
作者：
Finan C;Gaulton A;Kruger FA;Lumbers RT;Shah T;Engmann J;Galver L;Kelley R;Karlsson A;Santos R;Overington JP;Hingorani AD;Casas JP
通讯作者：
Casas JP
DOI：
10.1016/j.jinf.2020.11.031
发表时间：
2021-01
期刊：
The Journal of infection
影响因子：
--
作者：
Liu D;Yang J;Feng B;Lu W;Zhao C;Li L
通讯作者：
Li L
影响因子：
7.5
作者：
Jia, Haiyan;Thelwell, Craig;Wadhwa, Meenu
通讯作者：
Wadhwa, Meenu