ACE2gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population
ACE2gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population
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DOI：
10.1038/s41431-020-0691-z
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发表时间：
2020-07-17
影响因子：
5.2
通讯作者：
Pinto, Anna Maria
中科院分区：
文献类型：
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作者：
Benetti, Elisa;Tita, Rossella;Pinto, Anna Maria
2019年12月，中国武汉首次出现了间质性双侧肺炎。假设人与人之间的传播，并描述了一种以前未被识别的实体，即由新型冠状病毒（SARS-CoV-2）引起的冠状病毒病-19 （COVID-19）。感染迅速蔓延到世界各地，与亚洲国家相比，意大利是第一个经历临床严重程度出乎意料的流行浪潮的欧洲国家。研究表明，SARS-CoV-2利用血管紧张素转换酶2 （angiotensin converting enzyme 2, ACE2）作为宿主受体和宿主蛋白酶进行细胞表面结合和内化。因此，易感遗传背景可以解释个体间疾病的易感性和/或严重性。利用意大利基因组网络（Network of Italian Genomes， NIG），我们从5个不同的中心挖掘6930名意大利对照个体的全外显子组测序数据，寻找ace2变异。发现了许多对蛋白质稳定性有潜在影响的变异。其中，三种更常见的错义变化，p.(Asn720Asp), p.（Lys26Arg）和p.（Gly211Arg）被预测会干扰蛋白质结构和稳定性。还观察到可能干扰内化过程的罕见变异，即p.（Leu351Val）和p.(Pro389His)，预计会干扰SARS-CoV-2刺突蛋白的结合。比较131例患者和258例对照组的face2wes数据，发现对照组的等位基因变异性比患者高，具有统计学意义（p值< 0.029）。这些发现表明，易感遗传背景可能导致观察到的与COVID-19相关的个体间临床变异性，从而允许基于证据的风险评估，从而导致个性化的预防措施和治疗方案。
In December 2019, an initial cluster of interstitial bilateral pneumonia emerged in Wuhan, China. A human-to-human transmission was assumed and a previously unrecognized entity, termed coronavirus disease-19 (COVID-19) due to a novel coronavirus (SARS-CoV-2) was described. The infection has rapidly spread out all over the world and Italy has been the first European country experiencing the endemic wave with unexpected clinical severity in comparison with Asian countries. It has been shown that SARS-CoV-2 utilizes angiotensin converting enzyme 2 (ACE2) as host receptor and host proteases for cell surface binding and internalization. Thus, a predisposing genetic background can give reason for interindividual disease susceptibility and/or severity. Taking advantage of the Network of Italian Genomes (NIG), here we mined whole-exome sequencing data of 6930 Italian control individuals from five different centers looking forACE2variants. A number of variants with a potential impact on protein stability were identified. Among these, three more common missense changes, p.(Asn720Asp), p.(Lys26Arg), and p.(Gly211Arg) were predicted to interfere with protein structure and stabilization. Rare variants likely interfering with the internalization process, namely p.(Leu351Val) and p.(Pro389His), predicted to interfere with SARS-CoV-2 spike protein binding, were also observed. Comparison ofACE2WES data between a cohort of 131 patients and 258 controls allowed identifying a statistically significant (Pvalue < 0.029) higher allelic variability in controls compared with patients. These findings suggest that a predisposing genetic background may contribute to the observed interindividual clinical variability associated with COVID-19, allowing an evidence-based risk assessment leading to personalized preventive measures and therapeutic options.