Exploration of Genetic Variations in Vitamin D Metabolism and Susceptibility to Multiple Sclerosis: A Systematic Review and Meta-Analysis of CYP27B1 rs10877012 and CYP24A1 rs2248359 Gene Polymorphisms

Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease of the central nervous system characterized by inflammation, demyelination, and neurodegeneration. Although its exact etiology remains unclear, MS is considered a multifactorial disorder involving complex interactions between genetic susceptibility and environmental factors. Among the various environmental and biological factors implicated in MS development, vitamin D has attracted considerable attention because of its important immunomodulatory and neuroprotective properties. Vitamin D metabolism is regulated by several enzymes that control its synthesis, activation, and degradation, and genetic variations in the genes encoding these enzymes may influence individual susceptibility to MS. The present systematic review and meta-analysis aims to comprehensively investigate the association between genetic polymorphisms in two important vitamin D metabolism-related genes, CYP27B1 (rs10877012) and CYP24A1 (rs2248359), and susceptibility to multiple sclerosis. CYP27B1 encodes the 1α-hydroxylase enzyme responsible for converting 25-hydroxyvitamin D into its biologically active form, 1,25-dihydroxyvitamin D, whereas CYP24A1 encodes the 24-hydroxylase enzyme involved in vitamin D catabolism. Variations in these genes may alter vitamin D availability and metabolic regulation, potentially influencing immune responses and the pathophysiological mechanisms underlying MS. This study will systematically identify, evaluate, and synthesize relevant published case-control studies investigating the association between CYP27B1 rs10877012 and CYP24A1 rs2248359 polymorphisms and MS risk. A comprehensive literature search will be conducted across relevant electronic databases, including PubMed, Scopus, Web of Science, and other appropriate sources. Eligible studies will be selected according to predefined inclusion and exclusion criteria. Relevant data, including genotype distributions, allele frequencies, sample sizes, demographic characteristics, and reported effect estimates, will be extracted systematically. The methodological quality and risk of bias of the included studies will also be assessed using appropriate evaluation tools. A quantitative meta-analysis will be performed wherever sufficient comparable data are available. Pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) will be calculated to evaluate the associations under appropriate genetic models, including allelic, dominant, recessive, homozygous, and heterozygous models. Between-study heterogeneity will be assessed, and subgroup analyses, sensitivity analyses, and publication bias assessments will be conducted where appropriate. The expected outcomes of this study are to provide comprehensive evidence regarding the potential contribution of CYP27B1 rs10877012 and CYP24A1 rs2248359 genetic variations to MS susceptibility. The findings may help clarify the role of vitamin D metabolic pathways in the genetic architecture of MS, identify potentially relevant genetic risk markers, and highlight areas requiring further investigation. Ultimately, this research may contribute to a better understanding of the genetic mechanisms underlying MS susceptibility and provide a foundation for future studies on genetic risk assessment and personalized approaches to MS prevention and management.