Interaction between genetic, lifestyle and environmental factors determining circulating angiotensin-converting enzyme 2 protein expression: implications for the severity of COVID-19 infection

摘要 由新型冠状病毒2型(SARS-CoV-2)引起的2019年冠状病毒病(新冠肺炎)感染 全球超过1600万人，并在 过去七个月。几个患者亚组感染更严重新冠肺炎的风险更大，包括 高龄、肥胖或基础疾病(如糖尿病和心血管疾病)患者 疾病。实验数据支持ACE2受体在SARS的病理生理中的重要作用-- 冠状病毒2型感染。在疫情之前，ACE2蛋白水平一直是预测这种疾病的潜在生物标记物 以及预防心血管疾病和糖尿病。最近的研究表明，血清ACE2 在有心血管危险因素的患者中，与健康人相比，水平更高。这些 研究表明，ACE2水平升高可能是对心血管危险因素的代偿反应。 此外，据估计，循环血管紧张素转换酶2水平高达67%的变异性可由以下因素解释 遗传因素。还假设较高的ACE2蛋白水平可能与较高的 本地病毒载量。虽然不可能在人群中测量ACE2受体的组织密度 研究表明，新的更灵敏的分析方法现在可以测量ACE2的可溶性水平(SACE2)。数据来自我们的 基于人群的队列研究也支持这样一个事实，即sACE2水平与风险因素平行增加 与SARS-CoV-2感染的严重程度有关。在随机招募的544名参与者中 在普通人群中，我们观察到男性、老年受试者(55岁)和 那些胰岛素抵抗的人。新出现的数据还表明，污染可能通过以下两种方式之一调节疾病风险 增加患者的易感性或激活ACE2通路。研究与血管紧张素转换酶2改变相关的性状 表达及其循环水平可能会揭示为什么某些人更容易感染SARS- 关于CoV-2感染及其潜在机制的研究。这项研究的总体目标是深入了解 ACE2基因-环境相互作用与与SARS相关的环境和生活方式因素- 通过利用独特的基于人群和新冠肺炎的患者队列，预防CoV-2感染。我们假设 在允许的生活方式和环境因素存在的情况下，ACE2的遗传变异在 确定sACE2水平，因此将影响SARS-CoV-2的易感性和结局严重性 感染。我们将利用已经收集的流行病学队列和SARS-CoV-2患者队列从 美国和欧洲检测和验证一组常见的基因变异，包括SNPs和 影响ACE2蛋白水平及其与ACE2相互作用的简单和延伸单倍型 环境因素，包括饮食和空气污染。总体而言，我们将增加对ACE2的了解 基因变异、ACE2蛋白水平及其与包括饮食和空气在内的环境因素的相互作用 污染，与新冠肺炎疾病的易感性和严重程度直接相关。

SUMMARY The 2019 coronavirus disease (COVID-19) caused by the novel coronavirus 2 (SARS-CoV-2) has infected more than 16 million people worldwide and claimed the life of more than 650,000 persons worldwide within the past seven months. Several patient subgroups are at greater risk of more severe COVID-19 infection including patients with advanced age, obesity, or underlying disease such as diabetes mellitus (DM) and cardiovascular disease. Experimental data supports an important role of the ACE2 receptor in the pathophysiology of SARS- CoV-2 infection. Prior to the epidemic, ACE2 protein levels have been a potential biomarker for the prediction and prevention of cardiovascular diseases and diabetes. Recent studies have demonstrated that serum ACE2 level was higher in patients with cardiovascular risk factors as compared with healthy individuals. These studies suggest that elevated ACE2 levels may be a compensatory response to cardiovascular risk factors. Moreover, it was estimated that up to 67% of the variability in circulating ACE2 levels was explained by heritable factors. It was also hypothesized that higher ACE2 protein level might be associated with a higher local viral load. Although it is not possible to measure ACE2 receptor tissue density in population-based studies, new more sensitive assays now allow the measure of soluble levels of ACE2 (sACE2). Data from our population-based cohort also supports the fact that sACE2 levels increase in parallel with risk factors associated with severity of SARS-CoV-2 infection. In the cohort of 544 participants randomly recruited from the general population, we observed higher sACE2 levels in males, in older subjects (>55 years old), and in those with insulin resistance. Emerging data also suggest that pollution may modulate risk of disease by either increasing patient susceptibility or activating ACE2 pathways. Studying traits associated with altered ACE2 expression and its circulating levels may shed light on why certain individuals are more susceptible to SARS- CoV-2 infection and on the underlying mechanisms. The overall objective of this study is to gain insights on the ACE2 gene-environment interaction as it relates to environment and lifestyle factors associated with the SARS- CoV-2 infection by leveraging unique population-based and COVID-19 patient cohorts. We hypothesize that the genetic variants of ACE2 in the presence of permissive lifestyle and environmental factors play a role in determining sACE2 level and therefore will impact the susceptibility and outcome severity of the SARS-CoV-2 infection. We will utilize already collected epidemiological cohorts and SARS-CoV-2 patient cohorts from the United States and Europe to detect and validate a panel of common genetic variants, including SNPs and simple and extended haplotypes, which interfere with the ACE2 protein level and its interaction with environmental factors including diet and air pollution. Overall, we will increase our understanding of ACE2 gene variants, ACE2 protein level and their interaction with environmental factors, including diet and air pollution, that are directly associated with COVID-19 disease susceptibility and severity.