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Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19.
Gaziano, Liam; Giambartolomei, Claudia; Pereira, Alexandre C; Gaulton, Anna; Posner, Daniel C; Swanson, Sonja A; Ho, Yuk-Lam; Iyengar, Sudha K; Kosik, Nicole M; Vujkovic, Marijana; Gagnon, David R; Bento, A Patrícia; Barrio-Hernandez, Inigo; Rönnblom, Lars; Hagberg, Niklas; Lundtoft, Christian; Langenberg, Claudia; Pietzner, Maik; Valentine, Dennis; Gustincich, Stefano; Tartaglia, Gian Gaetano; Allara, Elias; Surendran, Praveen; Burgess, Stephen; Zhao, Jing Hua; Peters, James E; Prins, Bram P; Angelantonio, Emanuele Di; Devineni, Poornima; Shi, Yunling; Lynch, Kristine E; DuVall, Scott L; Garcon, Helene; Thomann, Lauren O; Zhou, Jin J; Gorman, Bryan R; Huffman, Jennifer E; O'Donnell, Christopher J; Tsao, Philip S; Beckham, Jean C; Pyarajan, Saiju; Muralidhar, Sumitra; Huang, Grant D; Ramoni, Rachel; Beltrao, Pedro; Danesh, John; Hung, Adriana M; Chang, Kyong-Mi; Sun, Yan V; Joseph, Jacob.
  • Gaziano L; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
  • Giambartolomei C; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Pereira AC; Central RNA Lab, Istituto Italiano di Tecnologia, Genoa, Italy.
  • Gaulton A; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
  • Posner DC; Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo, São Paulo, Brazil.
  • Swanson SA; Genetics Department, Harvard Medical School, Harvard University, Boston, MA, USA.
  • Ho YL; Chemical Biology, European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK.
  • Iyengar SK; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
  • Kosik NM; Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
  • Vujkovic M; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
  • Gagnon DR; Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA.
  • Bento AP; Department of Population and Quantitative Health Sciences, Case Western Reserve University and Louis Stoke, Cleveland VA, Cleveland, OH, USA.
  • Barrio-Hernandez I; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
  • Rönnblom L; The Corporal Michael J. Crescenz VA Medical Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Hagberg N; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Lundtoft C; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
  • Langenberg C; Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
  • Pietzner M; Chemical Biology, European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK.
  • Valentine D; European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK.
  • Gustincich S; Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
  • Tartaglia GG; Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
  • Allara E; Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
  • Surendran P; Berlin Institute of Health, Charité University Medicine Berlin, Berlin, Germany.
  • Burgess S; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
  • Zhao JH; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
  • Peters JE; Institute of Health Informatics, University College London, London, UK.
  • Prins BP; Health Data Research, University College London, London, UK.
  • Angelantonio ED; Central RNA Lab, Istituto Italiano di Tecnologia, Genoa, Italy.
  • Devineni P; Central RNA Lab, Istituto Italiano di Tecnologia, Genoa, Italy.
  • Shi Y; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Lynch KE; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • DuVall SL; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
  • Garcon H; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
  • Thomann LO; Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Zhou JJ; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Gorman BR; MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
  • Huffman JE; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • O'Donnell CJ; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
  • Tsao PS; Centre for Inflammatory Disease, Dept of Immunology and Inflammation, Imperial College, London, UK.
  • Beckham JC; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Pyarajan S; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
  • Muralidhar S; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Huang GD; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
  • Ramoni R; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
  • Beltrao P; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
  • Danesh J; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, UK.
  • Hung AM; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
  • Chang KM; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
  • Sun YV; VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
  • Joseph J; Department of Internal Medicine, Epidemiology, University of Utah, Salt Lake City, UT, USA.
Nat Med ; 27(4): 668-676, 2021 04.
Article in English | MEDLINE | ID: covidwho-1174686
Preprint
This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
See preprint
Semantic information from SemMedBD (by NLM)
1. Pharmaceutical Preparations INHIBITS Transcriptome
Subject
Pharmaceutical Preparations
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INHIBITS
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Transcriptome
2. Transcriptome LOCATION_OF COVID-19
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LOCATION_OF
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COVID-19
3. Radionuclide Imaging AFFECTS Hospitalization
Subject
Radionuclide Imaging
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AFFECTS
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Hospitalization
4. Pharmaceutical Preparations INTERACTS_WITH IFNAR2 gene|IFNAR2
Subject
Pharmaceutical Preparations
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INTERACTS_WITH
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IFNAR2 gene|IFNAR2
5. Pharmaceutical Preparations INTERACTS_WITH ACE2 gene|ACE2
Subject
Pharmaceutical Preparations
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INTERACTS_WITH
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ACE2 gene|ACE2
6. Pharmaceutical Preparations INHIBITS Transcriptome
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8. Radionuclide Imaging AFFECTS Hospitalization
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AFFECTS
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9. Pharmaceutical Preparations INTERACTS_WITH IFNAR2 gene|IFNAR2
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IFNAR2 gene|IFNAR2
10. Pharmaceutical Preparations INTERACTS_WITH ACE2 gene|ACE2
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ACE2 gene|ACE2
ABSTRACT
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 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-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci 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.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Mendelian Randomization Analysis / Drug Repositioning / SARS-CoV-2 / COVID-19 Type of study: Controlled clinical trial / Prognostic study Limits: Humans Language: English Journal: Nat Med Journal subject: Molecular Biology / Medicine Year: 2021 Document Type: Article Affiliation country: S41591-021-01310-z

Full text: Available Collection: International databases Database: MEDLINE Main subject: Mendelian Randomization Analysis / Drug Repositioning / SARS-CoV-2 / COVID-19 Type of study: Controlled clinical trial / Prognostic study Limits: Humans Language: English Journal: Nat Med Journal subject: Molecular Biology / Medicine Year: 2021 Document Type: Article Affiliation country: S41591-021-01310-z