Vitamin D Receptor Polymorphisms and Their Association with Nrf2-Dependent Gene Expression in Oxidative Stress...

The vitamin D receptor (VDR) exerts pleiotropic effects essential for human health and modulates the transcription of nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of the cellular antioxidant defense system. Polymorphisms represent a major source of interindividual variability and may influence susceptibility to oxidative stress. The VDR polymorphisms ApaI (A > C) and TaqI (T > C) have been associated with disease susceptibility; however, their role in oxidative stress responses during aging remains poorly understood. This study evaluated the association between ApaI and TaqI polymorphisms and susceptibility to oxidative stress-induced cell death, as well as the expression of genes within the VDR-Nrf2 signaling axis, in peripheral blood mononuclear cells (PBMCs) from cognitively healthy Chilean older adults. VDR genotyping was performed using real-time PCR (TaqMan SNP Genotyping Assay), PBMC viability following H₂O₂ exposure was assessed by flow cytometry, and gene expression levels were determined by quantitative PCR (qPCR). For ApaI, homozygous carriers of the A allele showed greater PBMC viability following H₂O₂ exposure (p < 0.0068) and higher mRNA expression levels of Nrf2 (p = 0.0176) and its downstream genes HMOX1 (p = 0.0070) and GST (p = 0.0047) compared with carriers of the C allele (AC or CC). For TaqI, homozygous carriers of the protective C allele exhibited greater PBMC viability (p < 0.0465) and higher Nrf2 (p = 0.0324), HMOX1 (p = 0.0206), and GST (p = 0.0029) expression compared with carriers of the risk T allele (TC or TT). These findings provide novel evidence that VDR polymorphisms may modulate antioxidant responses through regulation of Nrf2-dependent gene expression, suggesting a genetic determinant of oxidative stress resilience in cognitively healthy older adults.