The Disproportionate Effect of COVID-19 on African Americans

SARS-CoV-2 & the Renin-Angiotensin-Aldosterone System

Although the COVID-19 pandemic is winding down, the effects of the virus, both short-term and long-term, are still under heavy scrutiny. Of significant interest to researchers is the mortality discrepancy between different demographics. Namely, Black or African American, Non-Hispanic persons were over 2x more likely to be hospitalized with COVID-19 than White, Non-Hispanic persons, and 1.6x more likely to die from it. Although social factors have significant impacts on these statistical outcomes, inquiries concerning the roles of underlying complications are under investigation. The purpose of this research was to examine if there is a predisposition to complications resulting from a dysfunctional renin-angiotensin-aldosterone system in association with endothelial nitric oxide synthase uncoupling during COVID-19 infection in African Americans, leading to a greater risk of immunological and cardiovascular complications and death when compared to other ethnicities.

SARS-CoV-2

SARS-CoV-2 is the virus that causes COVID-19. SARS-CoV-2, along with other coronaviruses, are enveloped, positive-stranded RNA viruses. The envelope gives the virus significant protection, whereas the classification of its genetic information as positive-stranded RNA permits direct translation of the viral proteins in the ribosomes of the host cell. SARS-CoV-2 also has spike proteins, enabling it to recognize and bind to ACE2 receptors to infect an individual.

When SARS-CoV-2 enters the type II pneumocyte via ACE2, it hijacks the cell and utilizes it to synthesize multiple copies of itself. The type II pneumocyte eventually lyses and releases the newly formed copies of SARS-CoV-2. As a result of the damage caused to the type II pneumocytes, macrophages secrete certain inflammatory mediators that attract neutrophils to the alveoli. The neutrophils release specific chemicals attempting to destroy SARS-CoV-2, but also produce some collateral damage in the process, impairing the type II pneumocytes and the ACE2 receptors. This causes an overall decrease in the amount of ACE2 present in the alveolus (its molecular expression), thereby downregulating it.

Functional Renin-Angiotensin-Aldosterone System

Beyond being the port of entry for SARS-CoV-2, ACE2 serves a valuable physiological role. It is a key regulator of the renin-angiotensin-aldosterone system (RAAS), also sometimes known as the renin-angiotensin system (RAS), which works to stabilize blood pressure. The main molecule of the RAAS is angiotensin II. Angiotensin II is a vasoconstrictor and promotes the release of aldosterone. In other words, angiotensin II has properties to constrict blood vessels and increase blood volume content via water reabsorption, causing blood pressure to increase. Angiotensin II is eventually converted into angiotensin (1-7) by the protein ACE2. Angiotensin (1-7) is the antagonist of angiotensin II, reversing its potent effects. As readily seen, a smooth conversion of angiotensin II to angiotensin (1-7) is necessary to keep blood pressure from being consistently high. A continuous, increased presence of angiotensin II in the blood may cause persistent hypertension.

Dysfunctional Renin-Angiotensin-Aldosterone System

SARS-CoV-2 causes a systemic downregulation of ACE2 by destroying the type II pneumocytes that house this protein. With less ACE2 present to convert angiotensin II to angiotensin (1-7), abnormally high levels of angiotensin II leads to hypertension and other cardiovascular complications. This is a key underlying complication in African American patients that die from COVID-19. Moreover, the increased stimulation of angiotensin II inhibits the production of nitric oxide (NO), which acts as a vasodilator, dilating blood vessels, and also has antiviral properties, namely preventing SARS-CoV-2 from binding to ACE2. Since NO and angiotensin (1-7) production are inhibited, the functionality of the RAAS dangerously favors angiotensin II.

Gene Ontology Review

Both images indicate connections established between ACE2 and NOS3, the protein that enables nitric oxide production, through various other proteins. In the flowchart displayed, a description of each protein is mentioned, explaining whether there is an effect resulting from ACE2 downregulation.

Secondary Effects Caused by ACE2 Downregulation

Gene Ontology Heat Maps Depicting the Strength of Association Between Various Intersections

The four tables below are heat maps depicting the strength of associations between the respective intersections (genes of interest). The higher the adjusted p-value, the greater the confidence of the association. For example, for the first table, the relationship between the biological expressions of the genes ACE2, AGT, KNG1, NOS3 in the ACE inhibitor pathway is the most confident. The importance of this must be underlined, because it demonstrates the cascade effect that one dysregulation can have on multiple biological systems.

Table Comparing Hypertension Among Differing Ethnicities

The table below is drawn from Zhao et. al., 2014 and exhibits the prevalence of hypertension found in men and women from different ethnicities. The data demonstrate that Non-Hispanic Blacks have the highest rate of hypertension among the demographics listed in the article. Among various hypotheses is the idea that Non-Hispanic Blacks may have a lower molecular expression of ACE2 when compared to other ethnicities, which therefore establishes a correlation with the cardiovascular complications existing within the same people group.

Cycle Threshold Polymerase Chain Reaction

In order to conclude the hypothesis presented with the information from the table, a cycle threshold was extracted from De La Cruz et. al., 2021. The focus of the article was to compare the molecular expression of ACE2 between Blacks and Whites. It was found that Blacks have a higher cycle value compared to Whites, which is inversely proportional to the molecular expression of ACE2. Therefore, the study concluded that ACE2 is expressed more in Whites than in Blacks. Fewer ACE2 establishes a lower conversion rate of angiotensin II to angiotensin (1-7).

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