Synergistic IL-1 pathway genetic variants amplify susceptibility and inflammatory severity in COVID-19

Abstract Host genetic variation within the interleukin-1 (IL-1) signaling pathway may contribute to heterogeneity in COVID-19 susceptibility and disease outcomes and represents a potential target for precision risk stratification. We investigated whether polymorphisms in the IL-1 pathway influence SARS-CoV-2 infection risk and inflammatory responses. A hospital-based case–control study was conducted in Maharashtra, India, including 156 RT-PCR–confirmed COVID-19 patients and 154 SARS-CoV-2–negative controls. IL-1RN intron-2 VNTR (rs2234663) and IL-1β+3953C/T (rs1143634) polymorphisms were genotyped using PCR-based methods. Multivariable logistic regression was used to assess associations with COVID-19 susceptibility. Gene–gene interactions, haplotype analyses, genotype–biomarker correlations, and weighted Genetic Risk Score (GRS)-based models were evaluated. Carriers of the IL-1RN allele 2 and IL-1β T allele (driven primarily by the CT genotype) were associated with increased susceptibility to COVID-19. Multivariable analysis confirmed independent associations for IL-1RN allele 2 (OR 2.48, 95% CI 1.56–3.95) and IL-1β T allele (OR 3.12, 95% CI 1.92–5.07), primarily driven by the CT genotype. A significant gene–gene interaction between IL-1RN and IL-1β variants further increased susceptibility, indicating a synergistic genetic effect. Individuals carrying both risk alleles showed significantly higher CRP and ferritin levels, suggesting enhanced systemic inflammation. Incorporation of these variants into a Genetic Risk Score improved predictive performance compared with the clinical model alone (AUC 0.82 vs. 0.71). IL-1 pathway genetic variants are associated with COVID-19 susceptibility and inflammatory biomarker profiles. Integration of host genetic markers with clinical factors may improve risk stratification and support precision immunomodulatory strategies.