Genetic Variants within SARS-CoV-2 Human Receptor Genes May Contribute to Variable Disease Outcomes in Different Ethnicities

Abstract

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic, with an alarming infectivity and mortality rate. Studies have examined genetic effects on SARS-CoV-2 disease susceptibility and severity within Eurasian populations. These studies identified contrasting effects on the severity of disease between African populations. Genetic factors can explain some of the diversity observed within SARS-CoV-2 disease susceptibility and severity. Single nucleotide polymorphisms (SNPs) within the SARS-CoV-2 receptor genes have demonstrated detrimental and protective effects across ethnic groups. For example, the TT genotype of rs2285666 (Angiotensin-converting enzyme 2 (ACE2)) is associated with the severity of SARS-CoV-2 disease, which is found at higher frequency within Asian individuals compared to African and European individuals. In this study, we examined four SARS-CoV-2 receptors, ACE2, Transmembrane serine protease 2 (TMPRSS2), Neuropilin-1 (NRP1), and Basigin (CD147). A total of 42 SNPs located within the four receptors were reviewed: ACE2 (12), TMPRSS2 (10), BSG (CD147) (5), and NRP1 (15). These SNPs may be determining factors for the decreased disease severity observed within African individuals. Furthermore, we highlight the absence of genetic studies within the African population and emphasize the importance of further research. This review provides a comprehensive summary of specific variants within the SARS-CoV-2 receptor genes, which can offer a better understanding of the pathology of the SARS-CoV-2 pandemic and identify novel potential therapeutic targets.

Association of Renin-angiotensin pathway gene polymorphisms with COVID-19 susceptibility and severity in the Moroccan cohort

“…It is well known that SARS-CoV-2 uses the ACE2 receptor for cell entry, while the serine protease TMPRSS2 is required for priming of the viral spike (S) protein, which makes both coding genes strong candidates for susceptibility for SARS-CoV-2 infection (Hoffmann et al 2020;Dieter et al 2022). The most studied variants in these two genes in relation to COVID-19 outcomes were ACE2 rs2285666 and TMPRSS2 rs12329760, but the results have been controversial due to ethnicity, cohort size and variations in experimental protocols (Dieter et al 2022;Pecoraro et al 2023;Adimulam et al 2023). Our result showed that these two polymorphisms, whose prevalence were common (> 10%) and consistent with the hypothesis of common variants/common diseases for multifactorial diseases, were not associated with susceptibility and severity to COVID-19 infection.…”

“…Furthermore, emerging studies have indicated the involvement of SOX3 (SRY-Box Transcription Factor 3) in the regulation of ACE2 expression. Given its role as a transcription factor in early embryonic and neural development, alterations in SOX3 expression may in uence the susceptibility and severity of COVID-19, highlighting the potential link between developmental genes and viral pathogenesis (Araujo et Several studies have investigated, within various ethnic groups, the potential role of genetic variants, particularly in ACE2 and TMPRSS2 for their importance in the SARS-CoV-2 entry into cells, in COVID-19 susceptibility and severity (Adimulam et al 2023;Pecoraro et al 2023). However, few studies have focused concomitantly on all the RAS pathway genes for their potential in uence on viral entry, disease severity, and clinical outcomes, and results from these studies have been con icting (Gemmati et al 2020;Ca ero et al 2021).…”

The fatal contribution of serine protease-related genetic variants to COVID-19 outcomes

“…In this sense, the variants p.Gly8Val/c.23G>T (rs75603675) and p.Val197Met/c.589G>A (rs12329760) have been reported to influence its interaction with ACE2 and the S protein ( 29 , 31 , 32 ). rs2070788 has been reported to be highly expressed in the lungs of patients at risk of developing severe COVID-19 ( 33 ), suggesting that these variants could play an important role in the severity of SARS-CoV-2 infection ( 34 – 36 ). Nevertheless, the study of TMPRSS2 polymorphisms has been described in some populations with contradictory results ( 37 – 39 ).…”

Cytokine Kinetics during Progression of COVID-19 in Rwanda Patients: Could IL-9/IFNγ Ratio Predict Disease Severity?

“…The clinical manifestations of COVID-19, a viral infection due to SARS-CoV-2, vary from individual to individual and even between communities with different genetic backgrounds [1]. In particular, there is a wealth of evidence suggesting that COVID-19 was less severe in Africa compared to other continents, possibly due to demography, social economy, genetics, and a 'trained immunity' [2][3][4][5].…”

“…Although it is evident that immune responses play a significant role in COVID-19 clinical outcomes, the mechanisms underlying this heterogeneity are still elusive [15]. It is possible that genetic diversity can explain these variations [1], but the mechanistic characterisation of immune responses will help identify early markers of disease severity in different settings and populations.…”