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

Autor: 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, Leach, Andrew R, Edwards, Todd L, Cho, Kelly, Gaziano, J Michael, Butterworth, Adam S, Casas, Juan P, VA Million Veteran Program COVID-19 Science Initiative
Přispěvatelé: Epidemiology, Medical Research Council (MRC), Giambartolomei, Claudia [0000-0003-2786-1225], Gaulton, Anna [0000-0003-2634-7400], Posner, Daniel C [0000-0002-3056-6924], Kosik, Nicole M [0000-0003-1384-7035], Vujkovic, Marijana [0000-0003-4924-5714], Gagnon, David R [0000-0002-6367-3179], Bento, A Patrícia [0000-0003-1424-480X], Rönnblom, Lars [0000-0001-9403-6503], Hagberg, Niklas [0000-0003-2064-2716], Lundtoft, Christian [0000-0001-5872-4253], Langenberg, Claudia [0000-0002-5017-7344], Pietzner, Maik [0000-0003-3437-9963], Gustincich, Stefano [0000-0002-2749-2514], Tartaglia, Gian Gaetano [0000-0001-7524-6310], Allara, Elias [0000-0002-1634-8330], Burgess, Stephen [0000-0001-5365-8760], Peters, James E [0000-0002-9415-3440], Prins, Bram P [0000-0001-5774-034X], Huffman, Jennifer E [0000-0002-9672-2491], O'Donnell, Christopher J [0000-0002-2667-8624], Beltrao, Pedro [0000-0002-2724-7703], Chang, Kyong-Mi [0000-0001-6811-9364], Sun, Yan V [0000-0002-2838-1824], Butterworth, Adam S [0000-0002-6915-9015], Apollo - University of Cambridge Repository
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Biochemistry & Molecular Biology
Immunology
Quantitative Trait Loci
Druggability
Genome-wide association study
Receptor
Interferon alpha-beta
Computational biology
Research & Experimental Medicine
Quantitative trait locus
Biology
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
0302 clinical medicine
Mendelian randomization
Humans
VA Million Veteran Program COVID-19 Science Initiative
health care economics and organizations
11 Medical and Health Sciences
Repurposing
Science & Technology
RECEPTOR
SARS-CoV-2
Drug Repositioning
COVID-19
Cell Biology
IN-VITRO
General Medicine
Mendelian Randomization Analysis
Interleukin-10 Receptor beta Subunit
COVID-19 Drug Treatment
Drug repositioning
030104 developmental biology
Medicine
Research & Experimental
Drug development
030220 oncology & carcinogenesis
Expression quantitative trait loci
Angiotensin-Converting Enzyme 2
INTERFERON-ALPHA
Life Sciences & Biomedicine
Genome-Wide Association Study
Zdroj: Nature Medicine, 27(4), 668-676. Nature Publishing Group
Nature Medicine
ISSN: 1078-8956
DOI: 10.1038/s41591-021-01310-z
Popis: 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: OpenAIRE
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