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

遗传、生活方式和环境因素之间的相互作用决定循环血管紧张素转换酶 2 蛋白表达：对 COVID-19 感染严重程度的影响

• 批准号: 10228516
• 负责人: Kari C. Nadeau
• 金额: $ 22.94万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-16 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228516
• 关键词: 2019-nCoV; ACE2; Air Pollution; Biological Assay; Blood Pressure; COVID-19; COVID-19 patient; COVID-19 severity; COVID-19 susceptibility; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cells; Clinical; Coronavirus; Data; Diabetes Mellitus; Diet; Disease; Disease susceptibility; Drug or chemical Tissue Distribution; Elderly; Environment; Environmental Risk Factor; Epidemic; Epidemiology; Epithelial; Europe; Fibrinogen; Functional disorder; General Population; Genes; Genetic; Haplotypes; Heritability; Individual; Infection; Insulin Resistance; Kidney; Life; Light; Lung; Measures; Metabolic; Obesity; Outcome; Participant; Pathway interactions; Patients; Persons; Play; Pollution; Population; Population Study; Predisposition; Proteins; Rice; Risk; Risk Factors; Role; SARS coronavirus; SARS-CoV-2 infection; Serum; Severity of illness; Small Intestines; Subgroup; Testing; Testis; Tissues; United States; Vascular Endothelium; Viral Load result; Weight; cardiovascular disorder prevention; cardiovascular risk factor; cohort; density; disorder risk; experimental study; gene environment interaction; genetic variant; insight; lifestyle factors; male; multiple omics; novel; novel coronavirus; patient subsets; population based; potential biomarker; protein expression; receptor; recruit; response; severe COVID-19; trait

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.

概括 由新型冠状病毒 2 (SARS-CoV-2) 引起的 2019 冠状病毒病 (COVID-19) 已感染 全球超过 1,600 万人，并夺去了全球超过 650,000 人的生命 过去七个月。几个患者亚组面临更严重的 COVID-19 感染的风险更大，包括 高龄、肥胖或患有糖尿病（DM）和心血管等基础疾病的患者 疾病。实验数据支持 ACE2 受体在 SARS 病理生理学中的重要作用 CoV-2 感染。在疫情爆发之前，ACE2蛋白水平一直是预测的潜在生物标志物 以及预防心血管疾病和糖尿病。最近的研究表明，血清ACE2 与健康人相比，有心血管危险因素的患者的水平更高。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 ACE2 水平的变异性高达 67% 是由以下因素解释的： 遗传因素。还假设较高的 ACE2 蛋白水平可能与较高的 局部病毒载量。尽管不可能测量基于人群的 ACE2 受体组织密度 研究表明，新的更灵敏的检测现在可以测量 ACE2 (sACE2) 的可溶性水平。数据来自我们的 基于人群的队列也支持这样一个事实：sACE2 水平与危险因素同时增加 与 SARS-CoV-2 感染的严重程度相关。在 544 名参与者随机招募的队列中 在一般人群中，我们观察到男性、老年受试者（> 55 岁）和 那些有胰岛素抵抗的人。新数据还表明，污染可能通过以下任一方式调节疾病风险： 增加患者的易感性或激活 ACE2 通路。研究与 ACE2 改变相关的性状 表达及其循环水平可能有助于解释为什么某些个体更容易感染 SARS- CoV-2 感染及其潜在机制。本研究的总体目标是深入了解 ACE2基因-环境相互作用，因为它与与SARS相关的环境和生活方式因素有关 利用独特的基于人群的 COVID-19 患者队列来控制 CoV-2 感染。我们假设 在宽松的生活方式和环境因素存在下，ACE2 的遗传变异在 确定 sACE2 水平，因此将影响 SARS-CoV-2 的易感性和结果严重程度 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 美国和欧洲检测并验证一组常见的遗传变异，包括 SNP 和 简单和扩展的单倍型，干扰 ACE2 蛋白水平及其与 环境因素包括饮食和空气污染。总的来说，我们会增加对ACE2的了解 基因变异、ACE2 蛋白水平及其与环境因素（包括饮食和空气）的相互作用 污染，与 COVID-19 疾病的易感性和严重程度直接相关。