Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom.
Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China.
EBioMedicine. 2022 Jul;81:104112. doi: 10.1016/j.ebiom.2022.104112. Epub 2022 Jun 27.
Recent omic studies prioritised several drug targets associated with coronavirus disease 2019 (COVID-19) severity. However, little evidence was provided to systematically estimate the effect of drug targets on COVID-19 severity in multiple ancestries.
In this study, we applied Mendelian randomization (MR) and colocalization approaches to understand the putative causal effects of 16,059 transcripts and 1608 proteins on COVID-19 severity in European and effects of 610 proteins on COVID-19 severity in African ancestry. We further integrated genetics, clinical and literature evidence to prioritise drug targets. Additional sensitivity analyses including multi-trait colocalization and phenome-wide MR were conducted to test for MR assumptions.
MR and colocalization prioritized four protein targets, FCRL3, ICAM5, ENTPD5 and OAS1 that showed effect on COVID-19 severity in European ancestry. One protein target, SERPINA1 showed a stronger effect in African ancestry but much weaker effect in European ancestry (odds ratio [OR] in Africans=0.369, 95%CI=0.203 to 0.668, P = 9.96 × 10; OR in Europeans=1.021, 95%CI=0.901 to 1.157, P = 0.745), which suggested that increased level of SERPINA1 will reduce COVID-19 risk in African ancestry. One protein, ICAM1 showed suggestive effect on COVID-19 severity in both ancestries (OR in Europeans=1.152, 95%CI=1.063 to 1.249, P = 5.94 × 10; OR in Africans=1.481, 95%CI=1.008 to 2.176; P = 0.045). The OAS1, SERPINA1 and ICAM1 effects were replicated using updated COVID-19 severity data in the two ancestries respectively, where alternative splicing events in OAS1 and ICAM1 also showed marginal effects on COVID-19 severity in Europeans. The phenome-wide MR of the prioritised targets on 622 complex traits provided information on potential beneficial effects on other diseases and suggested little evidence of adverse effects on major complications.
Our study identified six proteins as showing putative causal effects on COVID-19 severity. OAS1 and SERPINA1 were targets of existing drugs in trials as potential COVID-19 treatments. ICAM1, ICAM5 and FCRL3 are related to the immune system. Across the six targets, OAS1 has no reliable instrument in African ancestry; SERPINA1, FCRL3, ICAM5 and ENTPD5 showed a different level of putative causal evidence in European and African ancestries, which highlights the importance of more powerful ancestry-specific GWAS and value of multi-ancestry MR in informing the effects of drug targets on COVID-19 across different populations. This study provides a first step towards clinical investigation of beneficial and adverse effects of COVID-19 drug targets.
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最近的组学研究优先考虑了与 2019 年冠状病毒病（COVID-19）严重程度相关的几个药物靶点。然而，几乎没有证据系统地评估药物靶点对多个祖裔 COVID-19 严重程度的影响。
在这项研究中，我们应用孟德尔随机化（MR）和共定位方法来了解 16059 个转录本和 1608 个蛋白质在欧洲对 COVID-19 严重程度的潜在因果效应，以及 610 个蛋白质在非洲祖裔对 COVID-19 严重程度的影响。我们进一步整合遗传学、临床和文献证据来优先考虑药物靶点。进行了额外的敏感性分析，包括多特征共定位和全表型 MR，以检验 MR 假设。
MR 和共定位优先考虑了四个蛋白质靶点，即 FCRL3、ICAM5、ENTPD5 和 OAS1，它们在欧洲祖裔中显示出对 COVID-19 严重程度的影响。一个蛋白质靶点 SERPINA1 在非洲祖裔中表现出更强的效应，但在欧洲祖裔中则弱得多（非洲人的比值比[OR]为 0.369，95%CI 为 0.203 至 0.668，P=9.96×10；欧洲人的 OR 为 1.021，95%CI 为 0.901 至 1.157，P=0.745），这表明 SERPINA1 水平升高将降低非洲祖裔 COVID-19 的风险。一种蛋白质 ICAM1 在两个祖裔中均显示出对 COVID-19 严重程度的提示性影响（欧洲人的 OR 为 1.152，95%CI 为 1.063 至 1.249，P=5.94×10；非洲人的 OR 为 1.481，95%CI 为 1.008 至 2.176；P=0.045）。使用两个祖裔中更新的 COVID-19 严重程度数据分别对 OAS1、SERPINA1 和 ICAM1 的效应进行了复制，其中 OAS1 和 ICAM1 的选择性剪接事件也显示出对欧洲人 COVID-19 严重程度的边缘效应。对优先考虑的目标进行的全表型 MR 对 622 种复杂特征进行了分析，提供了有关其他疾病潜在有益影响的信息，并表明对主要并发症几乎没有不良影响的证据。
我们的研究确定了六个蛋白质作为对 COVID-19 严重程度有潜在因果效应的蛋白质。OAS1 和 SERPINA1 是试验中现有药物的潜在 COVID-19 治疗靶点。ICAM1、ICAM5 和 FCRL3 与免疫系统有关。在这六个靶点中，OAS1 在非洲祖裔中没有可靠的工具；SERPINA1、FCRL3、ICAM5 和 ENTPD5 在欧洲和非洲祖裔中显示出不同程度的潜在因果证据，这突显了在不同人群中，进行更强大的祖裔特异性全基因组关联研究和多祖裔 MR 的重要性，以告知药物靶点对 COVID-19 的影响。本研究为临床研究 COVID-19 药物靶点的有益和不良反应提供了第一步。
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