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Principal Investigator: Kari C. Nadeau
Organization: STANFORD UNIVERSITY
Fiscal Year: 2021
Award: $229,449
Funding agency: National Institute of Environmental Health Sciences
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.
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