Beyond VDR: Vitamin D Metabolism Genes in Tuberculosis Susceptibility, Immune Response and Implications for Diabetes Mellitus.

BACKGROUND: Vitamin D is an important immunomodulator in host defense against Mycobacterium tuberculosis, yet most tuberculosis-related research has focused on the vitamin D receptor (VDR). The contribution of vitamin D metabolism genes, particularly cytochrome P450 (CYP) enzymes, remains less clearly defined. METHODS: We conducted a narrative review examining the role of major vitamin D-metabolizing enzymes, including CYP2R1, CYP27A1, CYP27B1, and CYP24A1, in tuberculosis susceptibility, immune regulation, and treatment response, with additional focus on diabetes mellitus as a major comorbidity. Evidence from genetic association studies, observational studies, mechanistic experiments, and clinical data was synthesized. RESULTS: Vitamin D metabolism enzymes influence intracellular vitamin D activation and inactivation, affecting antimicrobial peptide production, autophagy, cytokine signaling, and macrophage-mediated clearance of M. tuberculosis. Genetic and epigenetic variation in these pathways may contribute to differences in tuberculosis risk and prognosis. Diabetes mellitus may further disrupt these mechanisms through chronic hyperglycemia, oxidative stress, inflammation, impaired macrophage and T-cell function, and alterations in vitamin D metabolism, potentially increasing tuberculosis susceptibility and worsening outcomes. However, direct evidence for several enzymes remains limited. Inconsistent findings from vitamin D supplementation trials suggest that circulating 25(OH)D may not accurately reflect functional vitamin D activity at infection sites. Current evidence is largely mechanistic, observational, and genetic, with few interventional studies. CONCLUSION: Vitamin D metabolism genes represent an underexplored but potentially important component of tuberculosis pathophysiology, particularly in patients with diabetes. Future work should prioritize genetically stratified host-directed approaches to identify patients most likely to benefit from vitamin D-based interventions.