Vitamin D Receptor Polymorphisms and Their Association with Nrf2-Dependent Gene Expression in Oxidative Stress Resilience in Cognitively Healthy Aging

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.