Genetic mechanisms of critical illness in COVID-19
Genetic mechanisms of critical illness in COVID-19
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DOI：
10.1101/2020.09.24.20200048
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发表时间：
2020-09
期刊：
影响因子：
64.8
通讯作者：
E. Pairo-Castineira;S. Clohisey;L. Klarić;A. Bretherick;K. Rawlik;D. Pasko;S. Walker;N. Parkinson-N.-Parki
中科院分区：
文献类型：
--
作者：
E. Pairo-Castineira;S. Clohisey;L. Klarić;A. Bretherick;K. Rawlik;D. Pasko;S. Walker;N. Parkinson-N.-Parki
宿主介导的肺部炎症在2019冠状病毒病（COVID-19）引起的危重疾病中存在1，并导致死亡2。与危重病相关的宿主遗传变异可能会确定治疗开发的机制靶点3。在这里，我们报告了来自英国208个重症监护病房的2，244名COVID-19重症患者的GenOMICC（重症监护中死亡率遗传学）全基因组关联研究的结果。我们已经确定并复制了以下新的全基因组显著关联：染色体12q24.13（rs10735079，P = 1.65 × 10 − 8）在编码抗病毒限制性内切酶激活剂的基因簇中（OAS1、OAS2和OAS3）;位于染色体19p13.2（rs74956615，P = 2.3 × 10 − 8）靠近编码酪氨酸激酶2（TYK2）的基因;位于染色体19p13.3（rs2109069，P = 3.98 × 10 - 12）编码二肽基肽酶9（DPP 9）的基因内;在染色体21q22.1（rs2236757，P = 4.99 × 10 − 8）上存在干扰素受体基因IFNAR2。我们确定了许可药物再利用的潜在靶点：使用孟德尔随机化，我们发现IFNAR 2的低表达或TYK 2的高表达与危及生命的疾病相关的证据;肺组织中的全转录组相关性表明单核细胞-巨噬细胞趋化受体CCR 2的高表达与严重的COVID-19相关。我们的研究结果确定了与COVID-19中关键宿主抗病毒防御机制和炎症器官损伤介质相关的强大遗传信号。这两种机制可能适用于现有药物的靶向治疗。然而，在临床实践发生任何变化之前，大规模的随机临床试验将是必不可少的。一项针对COVID-19重症患者的全基因组关联研究确定了与重要的宿主抗病毒防御机制和炎症器官损伤介质相关的遗传信号，这些信号可能是重新利用药物治疗的目标。
Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10−8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice. A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.