Researchers at the Iowa State University have identified differences in gene expression levels between African Americans and European Americans that may explain the disproportionately higher rates of coronavirus disease 2019 (COVID-19) cases and related deaths among African Americans.
The authors say this differential gene expression should be researched further to establish risk factors and prognostic signatures that would guide more personalized treatment of COVID-19.
“By revealing differential expression of genes that may be key players in COVID-19 between African Americans and European Americans, we emphasize the importance of integrating gene expression into the mix of factors considered in studying this pandemic,” writes the team.
A pre-print version of the paper is available on bioRxiv*, while the article undergoes peer review.
Since its outbreak in Wuhan, China, late last year, the COVID-19 pandemic has reached almost every corner of the world, infecting more than 7.48 million people and causing almost 420,000 deaths.
The causative agent – severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – infects tissues lining the lungs, kidneys, and central nervous systems and causes a range of symptoms from fever, cough, and fatigue to renal failure, stroke, respiratory failure, and death.
Such symptoms are the result of the immune and inflammatory responses that occur in various regions of the body in response to host cell infection.
Risk factors for death are still not well understood
The factors that contribute to host morbidity and mortality are not well understood, but physiological aspects that have been identified include age, gender, obesity, and presence of comorbidities such as cardiovascular disease and diabetes.
Genetic factors are known to influence disease severity, but only a few are even partly understood.
Genetic variants in the host cell receptor that SARS-CoV-2 binds to – angiotensin-converting enzyme 2 (ACE2) – may influence the likelihood of viral host cell entry. Mutations in the Mediterranean Fever gene (MEFV) may boost levels of pro-inflammatory molecules and trigger a hyperinflammatory response called the cytokine storm, which is associated with increased disease severity.
SARS-CoV-2 viruses binding to ACE-2 receptors on a human cell, the initial stage of COVID-19 infection, conceptual 3D illustration credit: Kateryna Kon / Shutterstock By
The rate of COVID-19 cases and deaths is disproportionately higher among African Americans, which tends to be attributed to differences in socioeconomic factors.
However, the authors of the current study say a multitude of factors probably account for the disparity and that several studies have already pointed towards race-related differences in gene expression for other diseases.
Searching for genetic factors
Now, Urminder Singh and Eve Syrkin Wurtele have searched for differences in the expression of multiple genes implicated in COVID-19 severity between European Americans and Africa Americans.
The researchers re-mined a dataset of RNA-Seq samples modified from the GTEx (Genotype-Tissue Expression) Project and The Cancer Genome Atlas (TCGA).
“These large data provide a unique opportunity to evaluate differences in gene expression across populations in multiple organs in diseased and normal states,” they write.
The team focused on genes implicated in responses to SARS-CoV-2 infection and identified multiple genes involved in viral entry, endosomal movement, autophagy and inflammation that were differentially expressed between the two races.
Genes of interest
The researchers identified 11 genes of interest, including ones encoding serine proteases involved in priming SARS-CoV-2 for infection; interleukins involved in the cytokine storm and an enzyme involved in the metabolism of reactive oxygen species (ROS), which modulates immune responses against RNA viruses.
However, the team says one of the most notable findings was the differential expression in the genes F8A2 and F8A3. These genes encode a protein called HAP40, which is involved in early endosome motility and, therefore the endocytic pathway and autophagy.
SARS-CoV-2 mainly enters the host cell by attaching to the ACE2 receptor and then undergoing endocytosis (invagination into the host cell membrane). The resulting virus-containing endosome may release viral material or might fuse with vesicles called lysosomes or autophagosomes that degrade the viral cargo (autophagy). Therefore F8A2 and F8A3 may be involved in mediating early endosome movement and determining the fate of SARS-CoV-2.
The team reports that the expression of F8A2 was between 10 and 24 times higher among African Americans than among European Americans and that the expression of F8A3 was between 2.4 and 6.6 times higher.
Potential for prognostic signatures and precision treatment
The authors say their study showed significant differential expression of multiple COVID-19-related genes between African American and European American populations.
“By highlighting the wide-ranging differences in expression of several disease-related genes across populations, we emphasize the importance of harvesting this information for medicine,” write the researchers.
“Such population-informed research will establish prognostic signatures with vast implications for precision treatment of diseases such as COVID-19,” concludes the team.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.