Host determinants of inflammatory escalation remain incompletely defined in COVID-19. Vitamin D receptor (VDR) signaling regulates immune activation and cytokine responses, yet the contribution of VDR genetic variation to severe disease is unclear. We investigated two common VDR polymorphisms (rs7975232 and rs1544410) in a prospective, clinically stratified Indian cohort (
n
= 323), integrating genotype–phenotype associations, inflammatory biomarkers, interaction modeling, and polygenic risk stratification. Both variants were independently associated with severe disease under additive genetic models (per-risk allele adjusted OR 1.69 for rs7975232 and 1.82 for rs1544410) and demonstrated allele-dose relationships across severity categories. Risk alleles correlated with elevated IL-6, C-reactive protein, and ferritin levels, indicating amplified inflammatory signaling. A statistically significant gene–gene interaction between rs7975232 and rs1544410 (OR 2.48,
p
= 0.006) was observed; however, this finding should be considered exploratory pending independent replication. Vitamin D deficiency (< 20 ng/mL) further amplified genotype-associated risk, supporting a biologically relevant gene-environment interaction. Integration of genetic information into multivariable clinical models improved model discrimination within this cohort (AUC 0.83 vs. 0.72), although external validation is required. In silico functional annotation was performed using RegulomeDB, HaploReg, and GTEx (Supplementary Table S7). Together, these findings identify a genetically associated inflammatory risk profile characterized by VDR risk alleles, vitamin D deficiency, and heightened inflammatory responses, providing a framework for precision risk stratification targeting the vitamin D-VDR axis.
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.
