Association of IFN-γ +874 T/A Polymorphism With COVID-19 Susceptibility, Severity, and Inflammatory Response: A Case-Control Study From Southern Iran.

BACKGROUND: Significant interpatient variability in Coronavirus Disease 2019 (COVID-19) manifestations highlights the influence of host genetic factors on disease outcomes. This study examines its association with COVID-19 susceptibility, severity, and inflammatory markers in an Iranian population. METHODS: A retrospective case-control analysis was performed on 210 COVID-19 patients and 210 age- and sex-matched control subjects to evaluate whether the Interferon-gamma (IFN-γ) gene polymorphism (+874 T/A) is associated with disease severity. RESULTS: Patients had more comorbidities (e.g., diabetes 26.2% vs. 14.3%; hypertension 29.5% vs. 16.7%) and pronounced paraclinical abnormalities, including elevated Neutrophil-to-Lymphocyte Ratio (NLR) (8.1 vs. 1.9), C-reactive protein (CRP) (45.5 vs. 3.2 mg/L), and lymphopenia (1.1 vs. 2.1 × 103/μL; all p < 0.001). The TA genotype and A allele increased disease susceptibility (Odds Ratio (OR) =2.05 (95% CI: 1.32-3.19), p = 0.002; OR = 1.58 (95% CI: 1.11-2.25), p = 0.01, respectively). The TA genotype independently predicted severe disease (aOR = 2.85, p = 0.001), and both the TA and AA genotypes were linked to higher IL-6 levels (p < 0.001). TT carriers had shorter hospitalizations (p < 0.01). Combining TA/AA with NLR improved severity prediction (AUC = 0.82 (95% CI: 0.76-0.88)). CONCLUSION: The IFN-γ +874 TA genotype was independently associated with severe COVID-19. The TA genotype appears to confer increased risk of severe disease, whereas the AA genotype may be linked to a milder clinical presentation despite elevated inflammatory markers. Integration of genetic and hematological parameters may enhance risk stratification; however, further validation in larger and diverse populations is warranted.