IL10RB as a key regulator of COVID-19 host susceptibility and severity.
IL10RB as a key regulator of COVID-19 host susceptibility and severity.
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IL10RB 作为 COVID-19 宿主易感性和严重程度的关键调节因子。
DOI：
10.1101/2021.05.31.21254851
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Iyengar,Sudh
中科院分区：
文献类型：
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作者：
Voloudakis,Georgios;Hoffman,Gabriel;Venkatesh,Sanan;Lee,KyungMin;Dobrindt,Kristina;Vicari,JamesM;Zhang,Wen;Beckmann,NoamD;Jiang,Shan;Hoagland,Daisy;Bian,Jiantao;Gao,Lina;Corvelo,André;Cho,Kelly;Lee,JenniferS;Iyengar,Sudh
背景最近的努力已经确定了与2019冠状病毒病（COVID-19）感染率和疾病后果严重程度相关的遗传位点。将这些遗传发现转化为可药物化的基因和易于获得的化合物，以降低COVID-19宿主的易感性，这是下一步的关键。方法我们整合了COVID-19遗传易感性变体、多组织遗传调控基因表达（GReX）和干扰素标签，以鉴定逆转与COVID-19易感性相关的预测基因表达失调的候选基因和化合物。通过测试其GReX和观察到的血液转录组与COVID-19严重程度的相关性，以及通过体外扰动来量化对病毒载量和分子途径失调的影响，来验证最佳候选基因。我们通过基于流行病学证据检查最佳候选化合物是否降低COVID-19发病率来验证计算机药物重新定位分析。结果我们确定IL 10 RB是COVID-19宿主易感性的最关键调节因子。预测的GReX上调IL 10 RB和COVID-19患者血液中更高的IL 10 RB表达与更差的COVID-19结果相关。体外IL 10 RB过表达与病毒载量增加和免疫相关分子途径的激活相关。硫唑嘌呤和视黄醇被优先作为候选化合物，以降低COVID-19检测呈阳性的可能性。结论我们建立了一个综合的数据驱动的基因靶点优先级的方法。我们鉴定并验证了IL 10 RB作为调节COVID-19宿主易感性的合适分子靶标。最后，我们提供了一些现成的药物，将值得进一步调查的药物重新定位候选人的证据。
Background Recent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes and readily available compounds that reduce COVID-19 host susceptibility is a critical next step. Methods We integrate COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX) and perturbargen signatures to identify candidate genes and compounds that reverse the predicted gene expression dysregulation associated with COVID-19 susceptibility. The top candidate gene is validated by testing both its GReX and observed blood transcriptome association with COVID-19 severity, as well as by in vitro perturbation to quantify effects on viral load and molecular pathway dysregulation. We validate the in silico drug repositioning analysis by examining whether the top candidate compounds decrease COVID-19 incidence based on epidemiological evidence. Results We identify IL10RB as the top key regulator of COVID-19 host susceptibility. Predicted GReX up-regulation of IL10RB and higher IL10RB expression in COVID-19 patient blood is associated with worse COVID-19 outcomes. In vitro IL10RB overexpression is associated with increased viral load and activation of immune-related molecular pathways. Azathioprine and retinol are prioritized as candidate compounds to reduce the likelihood of testing positive for COVID-19. Conclusions We establish an integrative data-driven approach for gene target prioritization. We identify and validate IL10RB as a suitable molecular target for modulation of COVID-19 host susceptibility. Finally, we provide evidence for a few readily available medications that would warrant further investigation as drug repositioning candidates.