Background: Vitamin D is considered to play a role in multiple sclerosis (MS) etiopathogenesis. We recently identified a polymorphism in the CYP24A1 gene, rs2762943, that was associated with an increased MS risk. CYP24A1 encodes a protein involved in the catabolism of the active form of vitamin D. We investigated the immunological effects of carrying the rs2762943 risk allele, and its role as genetic modifier.
Methods: Serum levels of 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25(OH)₂D) were measured in a cohort of 167 MS patients. In a subgroup of patients, expression levels of MHC class II and co-stimulatory molecules were determined by flow cytometry, and serum levels of proinflammatory (IFNG, GM-CSF, CXCL13) and anti-inflammatory (IL-10) cytokines and neurofilament light chain were measured by single-molecule array assays. The effect of the rs2762943 polymorphism on disease activity and disability measures was evaluated in 340 MS patients.
Results: Compared to non-carriers, carriers of the rs2762943 risk allele were characterized by reduced levels of 1,25(OH)₂ D (p=0.0001), and elevated levels of IFNG (p=0.03) and GM-CSF (p=0.008), whereas no significant differences were observed for the other markers. The presence of the rs2762943 risk allele had no significant impact on disease activity and disability outcomes during follow-up. However, risk allele carriers were younger at disease onset (p=0.04).
Conclusions: These findings suggest that the CYP24A1 rs2762943 polymorphism plays a more important role on MS susceptibility than on disease prognosis, and is associated with lower 1,25(OH)₂ D levels and heightened pro-inflammatory environment in MS patients.