Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19.

Autor: Gaziano L; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Giambartolomei C; Central RNA Lab, Istituto Italiano di Tecnologia, Genoa, Italy.; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Pereira AC; Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo, São Paulo, Brazil.; Genetics Department, Harvard Medical School, Harvard University, Boston, MA, USA., Gaulton A; Chemical Biology, European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK., Posner DC; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA., Swanson SA; Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands., Ho YL; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA., Iyengar SK; Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA.; Department of Population and Quantitative Health Sciences, Case Western Reserve University and Louis Stoke, Cleveland VA, Cleveland, OH, USA., Kosik NM; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA., Vujkovic M; The Corporal Michael J. Crescenz VA Medical Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Gagnon DR; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.; Biostatistics, School of Public Health, Boston University, Boston, MA, USA., Bento AP; Chemical Biology, European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK., Barrio-Hernandez I; European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK., Rönnblom L; Department of Medical Sciences, Uppsala University, Uppsala, Sweden., Hagberg N; Department of Medical Sciences, Uppsala University, Uppsala, Sweden., Lundtoft C; Department of Medical Sciences, Uppsala University, Uppsala, Sweden., Langenberg C; Berlin Institute of Health, Charité University Medicine Berlin, Berlin, Germany.; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK., Pietzner M; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK., Valentine D; Institute of Health Informatics, University College London, London, UK.; Health Data Research, University College London, London, UK., Gustincich S; Central RNA Lab, Istituto Italiano di Tecnologia, Genoa, Italy., Tartaglia GG; Central RNA Lab, Istituto Italiano di Tecnologia, Genoa, Italy., Allara E; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Surendran P; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.; Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Burgess S; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; MRC Biostatistics Unit, University of Cambridge, Cambridge, UK., Zhao JH; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Peters JE; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.; Centre for Inflammatory Disease, Dept of Immunology and Inflammation, Imperial College, London, UK., Prins BP; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK., Angelantonio ED; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, UK., Devineni P; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA., Shi Y; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA., Lynch KE; VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT, USA.; Department of Internal Medicine, Epidemiology, University of Utah, Salt Lake City, UT, USA., DuVall SL; VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT, USA.; Department of Internal Medicine, Epidemiology, University of Utah, Salt Lake City, UT, USA., Garcon H; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA., Thomann LO; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA., Zhou JJ; Department of Epidemiology and Biostatistics, University of Arizona, Tucson, AZ, USA.; Phoenix VA Health Care System, Phoenix, AZ, USA., Gorman BR; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA., Huffman JE; Center for Population Genomics, Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA., O'Donnell CJ; Cardiology, VA Boston Healthcare System, Boston, MA, USA.; Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Tsao PS; Epidemiology Research and Information Center (ERIC), VA Palo Alto Health Care System, Palo Alto, CA, USA.; Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, USA., Beckham JC; MIRECC, Durham VA Medical Center, Durham, NC, USA.; Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA., Pyarajan S; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA., Muralidhar S; Office of Research and Development, Department of Veterans Affairs, Washington, DC, USA., Huang GD; Office of Research and Development, Department of Veterans Affairs, Washington, DC, USA., Ramoni R; Office of Research and Development, Department of Veterans Affairs, Washington, DC, USA., Beltrao P; European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK., Danesh J; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, UK., Hung AM; VA Tennessee Valley Healthcare System, Nashville, TN, USA.; Nephrology & Hypertension, Vanderbilt University, Nashville, TN, USA., Chang KM; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; The Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA., Sun YV; Atlanta VA Health Care System, Decatur, GA, USA.; Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA., Joseph J; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.; Medicine, Cardiovascular, VA Boston Healthcare System and Brigham & Women's Hospital, Boston, MA, USA., Leach AR; Chemical Biology, European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK., Edwards TL; Department of Veterans Affairs, Tennessee Valley Healthcare System, Vanderbilt University, Nashville, TN, USA.; Medicine, Epidemiology, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA., Cho K; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.; Division of Aging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Gaziano JM; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.; Division of Aging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Butterworth AS; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. asb38@medschl.cam.ac.uk.; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK. asb38@medschl.cam.ac.uk.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK. asb38@medschl.cam.ac.uk.; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK. asb38@medschl.cam.ac.uk.; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, UK. asb38@medschl.cam.ac.uk., Casas JP; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA. jpcasasromero@bwh.harvard.edu.; Division of Aging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. jpcasasromero@bwh.harvard.edu.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2021 Apr; Vol. 27 (4), pp. 668-676. Date of Electronic Publication: 2021 Apr 09.
DOI: 10.1038/s41591-021-01310-z
Abstrakt: 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.
Databáze: MEDLINE