Association of GSTM1 and GSTT1 Null Genotypes with Disease Severity and Serum Cytokine Levels in Hospitalized COVID-19 Patients

Background: The clinical course of COVID-19 is highly variable, ranging from asymptomatic infection to critical illness with hyperinflammation and multiorgan failure. Oxidative stress plays a central role in COVID-19 pathogenesis, and genetic polymorphisms in glutathione S-transferase (GST) enzymes, particularly GSTM1 and GSTT1 null genotypes, may impair antioxidant defense and exacerbate inflammatory responses. This study aimed to investigate the association of GSTM1 and GSTT1 null genotypes with both disease severity and serum cytokine levels in hospitalized COVID-19 patients. Methods: This cross-sectional study enrolled 137 COVID-19 patients hospitalized during the second pandemic wave (July–September 2020). Patients were stratified into mild (n = 67) and severe (n = 70) groups based on clinical criteria. GSTM1 and GSTT1 polymorphisms were determined by multiplex polymerase chain reaction. Serum levels of 13 cytokines were measured using flow cytometry. Logistic regression analyzed genotype associations with disease severity, and multivariate linear regression assessed relationships between null genotypes and pro-inflammatory cytokine levels (IL-6, TNF-α, IL-17A, IFN-γ), adjusted for age, sex, hypertension, and diabetes. Results: The GSTT1 null genotype was significantly associated with severe COVID-19 (adjusted OR = 2.56, 95% CI: 1.08–6.07, p = 0.032). Severe patients exhibited significantly elevated levels of IL-6 (75.6% increase, p = 0.008), TNF-α (69.4% increase, p = 0.005), IL-17A (54.4% increase, p = 0.016), and IFN-γ (10.1% increase, p = 0.021). Both GSTM1 and GSTT1 null genotypes were associated with higher levels of these cytokines, with stronger effects observed for GSTT1 null. In multivariate analysis, GSTT1 null independently predicted elevated IL-6 (β = 52.6, p = 0.003), TNF-α (β = 13.8, p = 0.002), IL-17A (β = 2.4, p = 0.001), and IFN-γ (β = 56.4, p = 0.012). The combined both null genotype showed the strongest associations but was limited by small sample size (n = 10) and should be interpreted with caution. Conclusions: The GSTT1 null genotype is associated with severe COVID-19 and appears to be associated with heightened pro-inflammatory cytokine responses, particularly IL-6, TNF-α, IL-17A, and IFN-γ. These findings suggest a potential role for genetic impairment of antioxidant defense may contribute to hyperinflammation in COVID-19 hyperinflammation, although validation in larger cohorts is needed.