Emad Ramadan

Background: The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in over 7 million confirmed deaths worldwide as of March 2024. This enveloped, single-stranded RNA virus belongs to the Nidovirus family and primarily causes respiratory illness, with symptoms ranging from subclinical manifestations to fatal outcomes like fever, cough, dyspnea, and fatigue.^1,2 Older individuals, those with underlying health conditions, and potentially males are at higher risk for severe disease.¹ SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptor for viral entry into target cells, leading to ACE2 downregulation and increased angiotensin II levels.^2,3 This mechanism contributes to lung injury by enhancing pulmonary vascular permeability. The widespread distribution of ACE2 receptors in extrapulmonary tissues like the heart, kidneys, endothelium, and intestine may explain the multi-organ dysfunction observed in severe COVID-19 cases.^1,2,3

Objective: Genetic and Molecular Factors Influencing COVID-19 Severity and Susceptibility Across Populations

Search Methods: An online search in the PubMed database was conducted from 2019 to 2023 using the following keywords: “COVID-19,” “Genetic factors affecting disease susceptibility and severity,” “Polymorphisms and COVID-19”

Results: Genome-wide association studies (GWAS) have identified two key genomic regions associated with increased risk of severe COVID-19 outcomes. The 3p21.31 locus, harboring immune genes like CXCR6, LZTFL1, SLC6A20, CCR9, and XCR1, doubled the risk of respiratory failure. The CXCR6 gene regulates lung-resident memory T cells critical for respiratory immunity.³ The SLC6A20 gene encodes a proline transporter that interacts with ACE2, while the LZTFL1 leucine zipper transcription factor gene impacts ciliogenesis and intracellular trafficking of ciliary proteins in airway epithelial cells. Multiple independent SNPs near these genes were associated with increased severity and susceptibility. The 9q34.2 region near the ABO gene also showed associations with disease severity.³ Further research highlighted the crucial role of the CXCR6/CXCL16 axis in COVID-19 immunopathogenesis.⁴ CXCL16, the ligand for CXCR6, promotes T cell chemotaxis and adhesion. Elevated plasma CXCL16 levels correlated with increased disease severity, potentially exacerbated by genetic variants upregulating CXCL16 expression and inflammatory cytokines like IFNγ and TNFα.⁴ This axis influences T cell homing to the lungs and localized cellular injury, particularly in lung pathology.⁴ In vitro studies revealed higher SARS-CoV-2 infection levels in cells with genetic defects in the type I interferon (IFN) pathway, a crucial antiviral defense mechanism.^5,6 Remarkably, transducing these defective cells with wild-type IRF7 or IFNAR1 genes reduced their susceptibility to infection.^5,6 Clinically, at least 10% of patients with life-threatening COVID-19 pneumonia had neutralizing auto-antibodies against type I IFNs, compromising this protective response.^5,6 Genetic variations in ACE2 and TMPRSS2 influenced COVID-19 susceptibility across populations. 63 potentially deleterious variants were identified in ACE2, and 68 in TMPRSS2, with varying distributions. The ACE2 p.Arg514Gly variant in African/African-American populations altered angiotensinogen-ACE2 interactions, associated with cardiovascular and pulmonary conditions.⁷ Prevalent TMPRSS2 polymorphisms like p.Val160Met linked to differential genetic susceptibility and risk factors. TMPRSS2 expression increases with age in lung epithelial cells, suggesting a potential link between its developmental regulation and age-related protection.⁷ Finally, ACE2 protein levels and SARS-CoV-2 spike protein binding were higher in individuals with blood types A and B compared to type O, indicating a potential vulnerability of blood group A individuals to infection.⁸ The binding of the spike protein to red blood cells was highest in blood type A and lowest in type O.⁸

Conclusions: Elevated CXCL16 levels in severe COVID-19 cases indicate an association with immune dysregulation and inflammatory responses. ACE2 and TMPRSS2 polymorphisms, play a significant role in determining susceptibility to COVID-19 and influencing disease severity. Type I IFN play a crucial role in mounting an effective immune response.  Finally, Blood type A was associated with an increased risk of SARS-CoV-2 infection, indicating a potential vulnerability of this blood group to the virus. These findings provide crucial insights into the genetic and molecular factors influencing COVID-19 severity and susceptibility across populations, paving the way for targeted therapeutic interventions and risk stratification strategies.

Works Cited:

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