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A Neanderthal OAS1 Isoform Protects Against COVID-19 Susceptibility and Severity: Results from Mendelian Randomization and Case-Control Studies
medRxiv - Genetic and Genomic Medicine Pub Date : 2020-12-24 , DOI: 10.1101/2020.10.13.20212092
Sirui Zhou , Guillaume Butler-Laporte , Tomoko Nakanishi , David Morrison , Jonathan Afilalo , Marc Afilalo , Laetitia Laurent , Maik Pietzner , Nicola Kerrison , Kaiqiong Zhao , Elsa Brunet-Ratnasingham , Danielle Henry , Nofar Kimchi , Zaman Afrasiabi , Nardin Rezk , Meriem Bouab , Louis Petitjean , Charlotte Guzman , Xiaoqing Xue , Chris Tselios , Branka Vulesevic , Olumide Adeleye , Tala Abdullah , Noor Almamlouk , Yiheng Chen , Michaël Chassé , Madeleine Durand , Michael Pollak , Clare Paterson , Hugo Zeberg , Johan Normark , Robert Frithiof , Miklós Lipcsey , Michael Hultström , Celia M T Greenwood , Claudia Langenberg , Elin Thysell , Vincent Mooser , Vincenzo Forgetta , Daniel E. Kaufmann , J Brent Richards

Proteins detectable in peripheral blood may influence COVID-19 susceptibility or severity. However, understanding which circulating proteins are etiologically involved is difficult because their levels may be influenced by COVID-19 itself and are also subject to confounding factors. To identify circulating proteins influencing COVID-19 susceptibility and severity we undertook a large-scale two-sample Mendelian randomization (MR) study, since this study design can rapidly scan hundreds of circulating proteins and reduces bias due to reverse causation and confounding. We identified genetic determinants of 931 circulating proteins in 28,461 SARS-CoV-2 uninfected individuals, retaining only single nucleotide polymorphism near the gene encoding the circulating protein. We found that a standard deviation increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (N = 4,336 cases / 623,902 controls; OR = 0.54, P = 7x10-8), COVID-19 hospitalization (N = 6,406 / 902,088; OR = 0.61, P = 8x10-8) and COVID-19 susceptibility (N = 14,134 / 1,284,876; OR = 0.78, P = 8x10-6). Results were consistent in multiple sensitivity analyses. We then measured OAS1 levels in 504 patients with repeated plasma samples (N=1039) with different COVID-19 outcomes and found that increased OAS1 levels in a non-infectious state were associated with protection against very severe COVID-19, hospitalization and susceptibility. Further analyses suggested that a Neanderthal isoform of OAS1 affords this protection. Thus, evidence from MR and a case-control study supported a protective role for OAS1 in COVID-19 outcomes. Available medicines, such as phosphodiesterase-12 inhibitors, increase OAS1 and could be explored for their effect on COVID-19 susceptibility and severity.

中文翻译:

尼安德特人OAS1亚型保护免受COVID-19敏感性和严重性:孟德尔随机化和病例对照研究的结果

外周血中可检测到的蛋白质可能会影响COVID-19的敏感性或严重性。但是,很难了解哪些循环蛋白在病因上涉及,因为它们的水平可能受到COVID-19本身的影响,并且还受混杂因素的影响。为了确定影响COVID-19敏感性和严重性的循环蛋白,我们进行了一项大规模的两样本孟德尔随机(MR)研究,因为该研究设计可以快速扫描数百种循环蛋白并减少由于反向因果关系和混杂而产生的偏倚。我们在28,461名SARS-CoV-2未感染个体中鉴定了931种循环蛋白的遗传决定因素,仅在编码循环蛋白的基因附近保留了单核苷酸多态性。我们发现OAS1水平的标准差增加与COVID-19死亡或通气减少(N = 4,336例/ 623,902对照; OR = 0.54,P = 7x10-8),COVID-19住院治疗(N = 6,406 / 902,088)有关; OR = 0.61,P = 8x10-8)和COVID-19磁化率(N = 14,134 / 1,284,876; OR = 0.78,P = 8x10-6)。多重敏感性分析结果一致。然后,我们测量了504例重复血浆样本(N = 1039)具有不同COVID-19结果的患者的OAS1水平,发现在非感染状态下增加的OAS1水平与预防非常严重的COVID-19,住院和易感性有关。进一步的分析表明,OAS1的穴居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结果中的保护作用。
更新日期:2020-12-24
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