Vitamin D receptor FokI polymorphism preferentially modulates cognitive vulnerability in Parkinson's disease: Evidence from an Indian cohort.

INTRODUCTION: Vitamin D deficiency (VDD) and neuroinflammation are emerging as key contributors in the pathophysiology of Parkinson's disease (PD). Characterized by both motor and non-motor symptoms, PD is marked by dopaminergic neuronal loss and α-synuclein accumulation. VD exerts neuroprotective effects by preserving dopaminergic neurons, enhancing neurotransmission, and reducing neuroinflammation. Its biological activity is primarily mediated through the Vitamin D Receptor (VDR), which functions as a transcription factor upon activation. This study investigates ethnic variability of two important VDR polymorphisms and their association with PD. METHODS: Literature revealed ethnic variations in the association between VDR polymorphisms and PD. 100 PD patients (Montreal Cognitive Assessment [MoCA ≤23]; H&Y ≤ 4) and 100 matched controls were genotyped for VDR-FokI (rs2228570) and VDR-BsmI (rs1544410) using PCR-RFLP, confirmed through sequencing. VD levels were quantified for 35 PD and 25 controls. RESULTS: Significant allelic differences were found in both FokI (C vs. T, p = 0.001) and BsmI (A vs. G, p = 0.002). Genotypic variation was significant in FokI (p = 0.003) and BsmI (p = 0.004). FokI genotypes correlated significantly with cognitive scores (MoCA, p = 0.03), with CT and TT genotypes associated with poorer outcomes. Further analysis showed males and patients with lower BMI, more vulnerable. FokI influence cognitive assessment in females. Hypovitaminosis D was prevalent in PD patients than controls. CONCLUSIONS: VDR-FokI (rs2228570) exhibits a significant association with cognitive vulnerability in PD cohort, emerging as a potential genetic risk marker, suggesting link between this variant and cognitive status. However, larger longitudinal cohorts are imperative to validate the prognostic utility of VDR and VD pathways. SIGNIFICANCE STATEMENT: Parkinson's disease (PD) is increasingly recognized as a multifactorial neurodegenerative disorder in which genetic susceptibility and modifiable environmental factors interact to influence disease progression. However, the contribution of vitamin D receptor (VDR) genetic variability to PD risk and cognitive dysfunction remains poorly understood, particularly in the Indian population. In this study, we demonstrate that two VDR polymorphisms, FokI (rs2228570) and BsmI (rs1544410), are significantly associated with PD, while vitamin D deficiency is more prevalent among affected individuals. Importantly, the FokI variant showed a strong association with cognitive impairment, with CT/TT carriers exhibiting significantly lower MoCA scores, identifying this polymorphism as a potential marker of cognitive vulnerability in PD. These findings advance our understanding of how vitamin D signalling influences neurodegeneration and cognitive decline, highlighting a biologically plausible gene-environment interaction in PD. Beyond movement disorders, this work underscores the broader relevance of vitamin D-dependent mechanisms in brain health and supports the development of genotype-informed precision medicine strategies for neurodegenerative diseases.