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科学家发现可用于COVID-19治疗的潜在药物
作者:小柯机器人 发布时间:2021/4/15 11:34:58

近日,美国哈佛医学院Juan P. Casas、英国剑桥大学Adam S. Butterworth等研究人员合作发现可用于COVID-19治疗的潜在药物。这一研究成果于2021年4月9日在线发表在国际学术期刊《自然—医学》上。

为了确定与COVID-19相关的治疗靶标,研究人员基于转录和蛋白质组学数据进行了孟德尔随机分析,为1,263种可操作蛋白(已获批准的药物或在临床开发阶段靶向)的遗传数据推导了遗传手段。使用来自Host Genetics Initiative和Million Veteran Program的摘要统计数据,研究人员分析了7,554例因COVID-19和超过100万例对照住院的患者。

通过使用顺式表达定量性状基因座遗传手段,研究人员发现了三种蛋白质(ACE2,P=1.6×10-6; IFNAR2,P=9.8×10-11和IL-10RB,P=2.3×10-14)的孟德尔显著随机化结果。为了弄清IL10RB和IFNAR2的共享表达定量性状基因座信号,研究人员进行了全基因组关联扫描和途径富集分析,并表明IFNAR2在COVID-19住院中更可能发挥作用。

这些发现表明,靶向IFNAR2和ACE2的药物可优先进行临床试验,以便用于COVID-19的早期治疗。

据介绍,药物重利用提供了一种快速的方法来满足治疗COVID-19的迫切需求。

附:英文原文

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

Author: Liam Gaziano, Claudia Giambartolomei, Alexandre C. Pereira, Anna Gaulton, Daniel C. Posner, Sonja A. Swanson, Yuk-Lam Ho, Sudha K. Iyengar, Nicole M. Kosik, Marijana Vujkovic, David R. Gagnon, A. Patrcia Bento, Inigo Barrio-Hernandez, Lars Rnnblom, Niklas Hagberg, Christian Lundtoft, Claudia Langenberg, Maik Pietzner, Dennis Valentine, Stefano Gustincich, Gian Gaetano Tartaglia, Elias Allara, Praveen Surendran, Stephen Burgess, Jing Hua Zhao, James E. Peters, Bram P. Prins, Emanuele Di Angelantonio, Poornima Devineni, Yunling Shi, Kristine E. Lynch, Scott L. DuVall, Helene Garcon, Lauren O. Thomann, Jin J. Zhou, Bryan R. Gorman, Jennifer E. Huffman, Christopher J. ODonnell, Philip S. Tsao, Jean C. Beckham, Saiju Pyarajan, Sumitra Muralidhar, Grant D. Huang, Rachel Ramoni, Pedro Beltrao, John Danesh, Adriana M. Hung, Kyong-Mi Chang, Yan V. Sun, Jacob Joseph, Andrew R. Leach, Todd L. Edwards, Kelly Cho, J. Michael Gaziano, Adam S. Butterworth, Juan P. Casas

Issue&Volume: 2021-04-09

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=1.6×106; IFNAR2, P=9.8×1011 and IL-10RB, P=2.3×1014) 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.

DOI: 10.1038/s41591-021-01310-z

Source: https://www.nature.com/articles/s41591-021-01310-z

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex