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Vitamin D pathway as a multi-level predictor of COVID-19 severity and mortality: Integrating serum levels, FokI (rs2228570) VDR polymorphism, and lung tissue expression

Year: 2025

Type: article

Abstract: BACKGROUND: Vitamin D is a known immunomodulator, but its predictive value in COVID-19 remains incompletely understood. This study investigates the role of vitamin D across molecular, biochemical, and histopathological levels to evaluate its association with COVID-19 severity and mortality. METHODS: A prospective case-control study was conducted in the Kurdistan Region of Iraq from May to October 2021. Ninety-five confirmed COVID-19 patients (75 survivors, 20 non-survivors) and 75 healthy controls were enrolled. Serum 25(OH)D levels were quantified by ELISA. Clinical severity was assessed using CURB-65, NEWS, and SOFA scores. Genotyping for the FokI (rs2228570) polymorphism in the VDR gene was performed via allele-specific PCR. Lung tissue from five survivors (biopsy) and five non-survivors (autopsy) underwent immunohistochemical staining to evaluate VDR expression. RESULTS: Serum vitamin D concentrations were markedly reduced in non-survivors (20.34 ± 0.46 ng/mL) relative to survivors (40.11 ± 0.28 ng/mL, p < 0.001). Vitamin D exhibited a negative correlation with CURB-65 (r = -0.828), NEWS (r = -0.794), and SOFA (r = -0.762) scores. Regression analysis established that vitamin D was independently associated with disease severity in our population. The TT genotype of the FokI VDR polymorphism correlated with markedly reduced vitamin D levels and elevated severity scores. Mortality exhibited a strong association with the TT genotype (OR = 10.29, 95 % CI: 2.204-49.19, p = 0.003) and the T allele (OR = 3.923, p = 0.0006). ROC analysis determined a vitamin D threshold of ≤ 20.56 ng/mL as indicative of mortality (AUC = 0.784, p < 0.0001). Immunohistochemistry demonstrated elevated VDR expression in lung tissues of deceased COVID-19 patients relative to VDR-negative controls. CONCLUSION: This study indicates that serum vitamin D levels, VDR gene polymorphism (rs2228570), and lung tissue VDR expression are strongly correlated with the severity and mortality of COVID-19. These findings validate the clinical use of vitamin D and VDR profiling may have associative markers and prospective treatment targets in the management of COVID-19.

Source: The Journal of Steroid Biochemistry and Molecular Biology

DOI: 10.1016/j.jsbmb.2025.106879