Vitamin D receptor gene variants and their association with clinical phenotypes of multiple sclerosis

Multiple sclerosis (MS) is a complex neuroinflammatory disorder shaped by environmental and genetic factors. Vitamin D, a well-known environmental factor associated with the disease, exerts its immunoregulatory effects mainly through vitamin D receptor (VDR). Single nucleotide variants (SNVs) within the VDR gene may modify receptor function. Although previous studies have examined VDR SNVs in patients with MS, results have been inconsistent. In addition, their involvement in disease phenotypic variability remains poorly understood. The study aimed to examine potential correlation between FokI (rs2228570), TaqI (rs731236), and BsmI (rs1544410) SNVs in VDR, and MS susceptibility, as well as clinical characteristics in a Southeastern European Caucasian case-control population. Genotypic analysis for the SNVs was performed using genomic DNA extracted from samples of 200 MS patients and 265 neurologically healthy controls. Statistical analysis indicated no significant associations between individual SNVs and MS susceptibility in univariate analyses. However, logistic regression showed a significant interaction between rs2228570 (CT) variant and rs731236 (AG), which remained after FDR correction (p_adj = 0.041). In genotype-phenotype analyses, the rs1544410 (AA) and rs731236 (GG) genotypes were associated with motor symptoms, after adjusting for sex and age. Furthermore, the rs731236 (AA) and rs1544410 (GG) genotypes were more frequent among patients without cervical spinal cord lesions. While the investigated VDR variants do not appear to independently influence MS susceptibility, specific genotype combinations and alleles may contribute to the clinical expression of the disease. These findings highlight the value of integrating interaction modelling and phenotype stratification in genetic studies. The results also support a potential role for vitamin D signalling in shaping MS heterogeneity.