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

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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.