Gene-environment interaction between VDR variants and vitamin D deficiency identifies a high-risk inflammatory phenotype associated with COVID-19 severity

Abstract

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.