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.

总结 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 全世界有1 600多万人死亡， 过去七个月几个患者亚组面临更严重的COVID-19感染风险，包括 高龄、肥胖或基础疾病（如糖尿病（DM）和心血管疾病）患者 疾病实验数据支持ACE 2受体在SARS病理生理学中的重要作用- CoV-2感染。在流行之前，ACE 2蛋白水平一直是预测的潜在生物标志物。 预防心血管疾病和糖尿病。最近的研究表明，血清ACE 2 有心血管危险因素的患者血浆中的p53水平高于健康人。这些 研究表明升高的ACE 2水平可能是对心血管危险因素的代偿反应。 此外，据估计，高达67%的循环ACE 2水平的变异性可以解释为： 遗传因素还假设较高的ACE 2蛋白水平可能与较高的 局部病毒载量。虽然不可能测量基于人群的ACE 2受体组织密度， 研究表明，新的更灵敏的检测方法现在可以测量可溶性ACE 2（sACE 2）水平。信息的途径 基于人群的队列研究也支持sACE 2水平与风险因素平行增加的事实 与SARS-CoV-2感染的严重程度相关。在随机招募的544名参与者中， 在一般人群中，我们观察到男性、老年受试者（>55岁）和 有胰岛素抵抗的人。新出现的数据还表明，污染可能通过以下方式调节疾病风险： 增加患者易感性或激活ACE 2通路。研究与ACE 2改变相关的特征 表达及其循环水平可能揭示为什么某些人更容易感染SARS- CoV-2感染及其潜在机制。本研究的总体目标是深入了解 ACE 2基因与环境的相互作用，因为它涉及与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COVID-19患者队列的CoV-2感染。我们假设 ACE 2的遗传变异在允许的生活方式和环境因素的存在下发挥作用， 确定sACE 2水平，因此将影响SARS-CoV-2的易感性和结局严重程度 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， 美国和欧洲检测和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ACE 2蛋白水平及其与 环境因素包括饮食和空气污染。总的来说，我们将增加对ACE 2的了解 基因变异、ACE 2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，这与COVID-19疾病的易感性和严重性直接相关。