Vitamin D and Genetic Susceptibility to Multiple Sclerosis: A Complex Biological Relationship
Multiple sclerosis (MS) is a complex immune-mediated disease of the central nervous system characterized by progressive damage to myelin. Although MS is not considered a directly inherited disease, genetic susceptibility contributes substantially to its development through interactions with epigenetic and environmental influences. The disease most commonly emerges in young adulthood and demonstrates marked sex-related differences, with prevalence substantially higher in women, although men may experience more rapid disability progression. Current evidence therefore supports a multifactorial model in which disruption of immune homeostasis arises from the combined effects of numerous biological and environmental determinants rather than from a single causal factor. One environmental factor that has attracted considerable scientific attention is vitamin D, particularly because reduced sunlight exposure and low circulating vitamin D concentrations have repeatedly been investigated in relation to MS susceptibility.
Vitamin D Metabolism and Biological Activity
Vitamin D exists principally as vitamin D₂, or ergocalciferol, and vitamin D₃, or cholecalciferol. Vitamin D₃ is produced predominantly in the skin after ultraviolet B radiation converts 7-dehydrocholesterol into pre-vitamin D₃, which subsequently rearranges into vitamin D₃; vitamin D₂ and smaller amounts of vitamin D₃ can also be obtained through dietary sources. As illustrated in the metabolic pathway presented on page 3 of the review, vitamin D must undergo two hydroxylation reactions before attaining full hormonal activity: the first occurs primarily in the liver and produces 25-hydroxyvitamin D [25(OH)D], while the second occurs mainly in the kidney and forms biologically active 1,25-dihydroxyvitamin D. Most circulating vitamin D metabolites are transported by vitamin D-binding protein (VDBP), and vitamin D then produces genomic effects through the vitamin D receptor (VDR) as well as non-genomic actions through membrane-associated receptors. These metabolic steps are controlled largely by cytochrome P450 enzymes, making the genes encoding these proteins biologically plausible candidates for influencing vitamin D status and, potentially, MS susceptibility.
How Vitamin D Could Influence Multiple Sclerosis Pathogenesis
The proposed relationship between vitamin D and MS extends beyond simple statistical associations. Numerous observational investigations reviewed by Scazzone and colleagues reported an inverse relationship between vitamin D status and MS risk, while Mendelian-randomization studies also provided evidence consistent with a possible causal contribution of low vitamin D concentrations. Several biological mechanisms may help explain this relationship. Vitamin D influences CD4⁺ T-helper-cell differentiation by reducing the development of pro-inflammatory Th1 and Th17 cells while favoring Th2 and regulatory T-cell responses. This is particularly relevant because activation of myelin-specific Th1 and Th17 populations contributes to inflammatory processes within the central nervous system. Vitamin D may also participate in myelination and remyelination by affecting oligodendrocyte precursor-cell differentiation and microglial clearance of damaged myelin. Furthermore, the review reports that vitamin D response elements occur in the promoter regions of many MS-associated genes, suggesting that inadequate vitamin D availability could potentially alter the expression of genes involved in disease susceptibility.
Genetic Control of Vitamin D Production: DHCR7/NADSYN1 and CYP2R1
Genetic variation can influence circulating 25(OH)D concentrations at several points in the vitamin D pathway. The DHCR7/NADSYN1 locus is particularly relevant because DHCR7 participates in the metabolic branch point connecting cholesterol synthesis with vitamin D₃ production. Genome-wide association studies identified variants within this genomic region as determinants of vitamin D status; however, studies investigating their relationship with MS have produced inconsistent findings. Some investigations identified associations between specific variants and vitamin D concentrations in patients with MS, whereas other case-control and sequencing studies detected no significant relationship with disease susceptibility. CYP2R1, which encodes a major hepatic vitamin D 25-hydroxylase, represents another important candidate. Several CYP2R1 variants have been examined, including rs10741657, rs10766197 and rs117913124. The latter was reported to be strongly associated with reduced 25(OH)D concentrations and increased odds of MS in one study, while rs10766197 was associated with vitamin D status and both MS risk and progression in another investigation. Nevertheless, some of these findings have not been independently replicated, emphasizing the difficulty of assigning a definitive disease effect to individual polymorphisms.
CYP27B1 and CYP24A1: Activation and Degradation of Vitamin D
Two additional genes are biologically important because they regulate opposing stages of vitamin D metabolism. CYP27B1 encodes the enzyme responsible for converting 25(OH)D into active 1,25-dihydroxyvitamin D, and genetic evidence has repeatedly drawn attention to this locus. Genome-wide association and family-based studies identified several CYP27B1 variants associated with MS, including rare loss-of-function variants capable of reducing production of active vitamin D. The accumulated evidence led the review authors to consider CYP27B1 a potentially important component of MS genetic susceptibility, although not every reported variant has been independently confirmed. In contrast, CYP24A1 encodes an enzyme responsible for vitamin D catabolism. The rs2248359 variant was identified among MS susceptibility loci in a large genome-wide association study, and subsequent work provided evidence that it can regulate CYP24A1 expression in human brain tissue. Nevertheless, several studies involving Canadian, Chinese, Danish and Tasmanian populations failed to detect significant associations, leaving the contribution of CYP24A1 polymorphisms unresolved.
Vitamin D Transport and Signaling: VDBP and the VDR Pathway
Vitamin D-related genetic susceptibility is not limited to metabolic enzymes. VDBP, encoded by the GC gene, transports the majority of circulating vitamin D metabolites and contains highly studied polymorphisms such as rs7041 and rs4588. These variants produce VDBP isoforms with different binding characteristics and can influence circulating 25(OH)D concentrations. Nevertheless, studies reviewed in the article generally failed to demonstrate a consistent direct association between VDBP polymorphisms and MS risk, suggesting that their effects may operate principally through modification of vitamin D status rather than through a strong independent influence on disease susceptibility. The VDR gene has received substantially greater research attention. Commonly studied polymorphisms include FokI, ApaI, BsmI and TaqI, yet results across populations have often been contradictory. Differences in sample size, statistical power, clinical heterogeneity and interactions with other genetic or environmental factors may partially explain these inconsistencies. Consequently, although VDR remains the most extensively investigated vitamin D-related gene in MS, its precise contribution to disease susceptibility remains debated.
Scientific Interpretation and Future Directions
The available evidence portrays the relationship between vitamin D genetics and MS as biologically compelling but scientifically unresolved. The review examined single-nucleotide polymorphisms across 12 genes involved in vitamin D metabolism, transport and signaling and concluded that existing studies cannot yet establish precisely whether, or to what extent, vitamin D-related genetic variants determine MS risk. MS is better understood as a polygenic disorder in which individual variants generally exert modest effects that interact with environmental exposure, epigenetic mechanisms and other regulatory processes. Accordingly, no single vitamin D-related polymorphism can presently be regarded as a definitive genetic determinant of MS. The strongest body of evidence concerns VDR, while genes such as CYP27B1, CYP24A1, CYP2R1 and others require further investigation and independent replication. The authors nevertheless propose that a better understanding of genetic determinants of vitamin D status could eventually contribute to identifying susceptible individuals and may support more personalized approaches to prevention, disease management and treatment.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Scazzone, C., Agnello, L., Bivona, G. et al. Vitamin D and Genetic Susceptibility to Multiple Sclerosis. Biochem Genet 59, 1–30 (2021). https://doi.org/10.1007/s10528-020-10010-1
