Antioxidant Enzyme Polymorphisms and their Association with the Severity of COVID-19

The clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, leading to COVID-19, exhibits a spectrum of manifestations ranging from asymptomatic to severe. Identifying patients at increased risk of developing severe disease remains a challenge, despite known risk factors.

Recent studies have underscored the significance of oxidative stress in the progression of COVID-19, suggesting a pivotal role in various disease processes. This article explores the intricate interplay between genetic polymorphisms of regulatory and catalytic antioxidant proteins and the severity of COVID-19, shedding light on their independent and synergistic effects with conventional laboratory parameters.

Introduction
The heterogeneity in the clinical presentation of COVID-19 poses a significant hurdle in predicting disease severity, urging the need for novel predictive markers. This article delves into the molecular landscape, emphasizing the role of oxidative stress and its correlation with the severity of SARS-CoV-2 infection. Focusing on the genetic variants within antioxidant enzymes, we aim to unravel their impact on disease outcomes.

Clinical Manifestations and Risk Factors:
The severity of COVID-19 is influenced by a myriad of factors, including arterial hypertension, diabetes mellitus, renal impairment, certain malignancies, age, and gender. However, a subset of patients devoid of these risk factors still succumb to severe forms of the disease, emphasizing the need for additional predictive markers.

Biochemical Markers in COVID-19 Monitoring:
Several biochemical markers emerge as vital tools in monitoring and prognosticating COVID-19 patients. Inflammation parameters (IL-6, CRP, fibrinogen), leucocyte count, platelets, markers of tissue damage (urea, creatinine, transaminases, LDH), and coagulation parameters (fibrinogen and d-dimer) collectively aid in identifying patients at increased risk of severe disease.

Oxidative Stress in COVID-19 Pathogenesis:
Oxidative stress assumes a central role in the pathogenesis of severe acute respiratory failure in SARS-CoV-2 infection. The virus, akin to other RNA viruses, is implicated in inducing oxidative stress, contributing to an enhanced inflammatory response and tissue damage. The imbalance between free radical production, predominantly reactive oxygen species (ROS), and insufficient antioxidant mechanisms further exacerbates the severity of clinical manifestations.

Antioxidant Systems and Genetic Variability:
The human body employs a multitude of non-enzymatic and enzymatic antioxidant systems to safeguard against oxidative damage. Enzymes like superoxide dismutase (SOD), glutathione peroxidase (GPX), and glutathione transferase (GST) play pivotal roles.

The transcription factor Nrf2 regulates antioxidant enzyme expression, and its decreased expression in COVID-19 patients has been observed. Genetic heterogeneity, including deletion polymorphisms and single-nucleotide polymorphisms (SNPs), within genes encoding these antioxidant proteins, introduces variability in their structure, function, and expression.

Genetic Impact on COVID-19 Severity:
Recent studies have identified associations between genetic polymorphisms in antioxidant enzyme genes, including GSTP1, GSTM3, GSTO1, and GSTO2, with the likelihood of contracting COVID-19 and developing specific clinical manifestations. The GSTT1 null genotype has been correlated with increased mortality. Variations in genes encoding regulatory and catalytic antioxidant proteins directly influence protein activity, substrate diversity, and ultimately impact disease outcomes.

Discussion: Decoding the Genetic Tapestry of COVID-19 Severity

The exploration of oxidative stress and its connection to COVID-19 severity has led us to delve into the intricate genetic landscape of catalytic and regulatory antioxidant proteins. While our initial hypothesis suggested a potential modulation of disease severity, our findings paint a nuanced picture, uncovering associations and disparities in the genetic profiles of COVID-19 patients.

Inflammatory Markers and Disease Progression: Our study corroborates the importance of inflammatory markers as predictors of COVID-19 severity. Lymphocyte count, CRP, and IL-6 levels emerged as key indicators, aligning with established literature. The meta-analyses conducted by Henry BM et al. and Huang I et al. underscored the significance of elevated white blood cell count, decreased lymphocyte count, and increased levels of inflammatory markers in predicting severe outcomes. This convergence emphasizes the robustness of these markers across diverse populations.

Laboratory Parameters and Organ Damage: In parallel, our findings underscore the prognostic value of laboratory markers indicative of organ damage. Elevated levels of AST and LDH on admission align with studies by Battaglini D et al., reinforcing their correlation with clinical severity. Additionally, large-scale meta-analyses further support the association between cardiac biochemical markers, including LDH, and the severity of COVID-19. These markers provide valuable insights into the multi-organ impact of the virus and aid in risk stratification.

Genetic Variability and Disease Severity: Despite the established links between oxidative stress and COVID-19, our study did not find a significant association between null/variant genotypes of antioxidant proteins and the risk of developing severe forms of the disease. This contrasts with studies by Abbas M et al. and Saadat M et al., which reported associations between GSTM1−/−, GSTT1−/−, and severe COVID-19, suggesting potential population-specific variations. The Polish study by Orlewska K et al. aligns with our findings regarding GSTM1 and GSTT1 null genotypes.

GPX3 Variant Allele and Severity: A notable exception was the association found between the GPX3 rs8177412 variant allele and an increased risk of severe COVID-19. This variant, linked to reduced plasma GPX3 activity, adds a unique dimension to our understanding. The extracellular localization of GPX3, its role in scavenging oxidative species, and the impact on endothelial function provide a compelling narrative linking this genetic variant to the pathophysiology of COVID-19.

Limitations and Considerations: Acknowledging the limitations of our study, including a relatively small sample size and the assessment of selected genetic variants, prompts caution in generalizing the findings. The study’s focus on specific virus variants during the second wave in Serbia adds another layer of complexity, necessitating a broader exploration across diverse viral strains. Recovery time and other potential confounding factors were not fully accounted for, prompting avenues for future research.

Conclusion:
This study endeavors to deepen our understanding of the intricate relationship between inflammation and oxidative stress in the context of SARS-CoV-2 infection. By examining the association of genetic polymorphisms of antioxidant enzymes with COVID-19 severity, both independently and in conjunction with conventional laboratory parameters, we aim to contribute valuable insights for risk assessment and prognosis, paving the way for more targeted and personalized approaches to managing this global health crisis.