A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity
A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity
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DOI：
10.1038/s41591-021-01281-1
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发表时间：
2021-02-25
期刊：
影响因子：
82.9
通讯作者：
Richards, J. Brent
中科院分区：
文献类型：
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作者：
Zhou, Sirui;Butler-Laporte, Guillaume;Richards, J. Brent
为了确定影响 2019 冠状病毒病 (COVID-19) 易感性和严重程度的循环蛋白，我们进行了两个样本孟德尔随机化 (MR) 研究，快速扫描了数百种循环蛋白，同时减少了因反向因果关系和混杂因素造成的偏差。在多达 14,134 个病例和 120 万个对照中，我们发现 s.d. OAS1水平的增加与COVID-19死亡或通气（比值比（OR）= 0.54，P = 7 x 10(-8)）、住院（OR = 0.61，P = 8 x 10(-8)）和易感性（OR = 0.78，P = 8 x 10(-6)）减少相关。通过测量 504 名个体的 OAS1 水平，我们发现非感染状态下血浆 OAS1 水平较高与 COVID-19 易感性和严重程度降低相关。进一步的分析表明，欧洲血统个体中 OAS1 的尼安德特人亚型提供了这种保护。因此，来自 MR 和病例对照研究的证据支持 OAS1 在 COVID-19 不良后果中的保护作用。可以优先考虑提高 OAS1 水平的可用药物进行药物开发。OAS1 基因的一种变体编码一种酶，这种酶对于病毒感染的先天免疫反应至关重要，与 COVID-19 患者的死亡风险降低有关。
To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 x 10(-8)), hospitalization (OR = 0.61, P = 8 x 10(-8)) and susceptibility (OR = 0.78, P = 8 x 10(-6)). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case-control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.A variant of the OAS1 gene, which encodes an enzyme that is critical for the innate immune response to viral infections, is associated with decreased risk of death in patients with COVID-19.