Vitamin D genes associated with Multiple Sclerosis
Vitamin D Metabolism Dysfunction in Multiple Sclerosis – Perplexity AI Aug 2025
MS demonstrates a complex multi-component dysfunction in vitamin D metabolism rather than simple VDR deactivation. The poor vitamin D metabolism in MS involves several critical components working in combination to create a state of functional vitamin D deficiency despite adequate or even increased VDR expression.
Primary Enzyme Defects
CYP27B1 (1-alpha-hydroxylase) - The Most Significant Factor
The strongest genetic evidence for vitamin D metabolism dysfunction in MS comes from CYP27B1 defects:
Rare Loss-of-Function Mutations : Five variants identified in MS patients with 4.7-fold increased MS risk (95% CI: 2.3-9.4; p = 5×10⁻⁷) pmc.ncbi.nlm.nih+1
Perfect Transmission Pattern : These mutations were transmitted from heterozygous parents to MS offspring 35 out of 35 times (p = 3×10⁻⁹) onlinelibrary.wiley
Rickets Connection : Known vitamin D-dependent rickets type I (VDDR1) mutations found in MS patients jamanetwork+1
Functional Impact : Even heterozygous carriers have reduced calcitriol production onlinelibrary.wiley
Carrier Frequency : 0.67% in MS patients versus much lower in controls pmc.ncbi.nlm.nih
CYP2R1 (25-hydroxylase) - Moderate Impact
This enzyme converts vitamin D₃ to the storage form 25(OH)D:
Polymorphism rs10766197 : The A allele significantly increases MS risk pubmed.ncbi.nlm.nih+1
Genotype Effect : GA+AA carriers showed increased MS risk (p = 0.03) compared to controls pubmed.ncbi.nlm.nih
Serum Impact : Associated with lower 25(OH)D levels in carriers pubmed.ncbi.nlm.nih
CYP24A1 (24-hydroxylase) - Dysregulated Degradation
This enzyme normally degrades vitamin D metabolites but becomes dysregulated in MS:
Brain Expression : Restricted to astrocytes in MS lesions, suggesting localized vitamin D degradation pubmed.ncbi.nlm.nih
Upregulation : Increased expression in chronic active MS lesions pubmed.ncbi.nlm.nih
Genetic Variants : rs2248137 polymorphism associated with MS risk nature+1
Functional Effect : CC genotype carriers have significantly lower 25(OH)D levels pmc.ncbi.nlm.nih
Vitamin D Binding Protein (DBP) Deficiency
DBP dysfunction represents a major component of MS vitamin D metabolism problems:
Quantified Reductions
Serum Levels : Significantly lower in MS patients versus healthy controls pmc.ncbi.nlm.nih+1
Disease Activity : Lowest levels during relapsing-remitting MS relapses pmc.ncbi.nlm.nih
Newly Diagnosed Patients : Most pronounced DBP deficiency in drug-naïve patients pmc.ncbi.nlm.nih
Synergistic Effects
Combined Risk : Low DBP + low 25(OH)D creates 2.67-fold increased MS risk (95% CI: 1.35-5.29; p = 0.005) pmc.ncbi.nlm.nih
Protective Role : Higher DBP levels appear to protect against hypovitaminosis D-mediated MS risk pmc.ncbi.nlm.nih
CSF Correlation : DBP levels in cerebrospinal fluid correlate with MS disease course psych.ox
Mechanistic Impact
Megalin Pathway : Reduced renal reabsorption of the DBP-25(OH)D complex pmc.ncbi.nlm.nih
Bioavailability : Lower DBP may reduce free and bioavailable vitamin D levels pmc.ncbi.nlm.nih
Tissue Delivery : Impaired vitamin D delivery to target tissues including the brain pmc.ncbi.nlm.nih
Tissue-Specific Changes in MS Brain
MS brain tissue shows compensatory increases in vitamin D metabolism components:
Active Lesions : Increased VDR and CYP27B1 mRNA expression pubmed.ncbi.nlm.nih
Astrocytes : Show both nuclear and cytoplasmic VDR staining, plus restricted CYP24A1 expression pubmed.ncbi.nlm.nih
Oligodendrocytes : Display nuclear VDR staining pubmed.ncbi.nlm.nih
Microglia : HLA-positive microglia show nuclear VDR staining pubmed.ncbi.nlm.nih
Clinical Consequences
This multi-component dysfunction creates several clinical patterns:
Serum Vitamin D Status
Deficiency Prevalence : Approximately 50% of MS patients in Europe have vitamin D insufficiency pmc.ncbi.nlm.nih
Disease Correlation : Lower 25(OH)D levels early in disease predict worse long-term outcomes jamanetwork
Dose Requirements : MS patients may need higher vitamin D doses due to metabolic inefficiency
Treatment Response
High-Dose Requirements : Some studies use 50,000 IU weekly, suggesting normal doses are insufficient pubmed.ncbi.nlm.nih
Paradoxical Responses : High-dose vitamin D can paradoxically decrease VDR expression pubmed.ncbi.nlm.nih
Genetic Stratification : Treatment response may depend on specific genetic variants pubmed.ncbi.nlm.nih
Estimated Dysfunction Impact (Table)
Based on the research evidence, the proportion of MS patients with various vitamin D metabolism defects:
| ComponentAffected | Percentage | Impact Level |
| CYP27B1 mutations | 0.67% of MS patients pmc.ncbi.nlm.nih | 4.7-fold MS risk onlinelibrary.wiley |
| CYP2R1 polymorphisms | Variable frequency | Increased risk in carriers pubmed.ncbi.nlm.nih |
| DBP deficiency | Majority of MS patients pmc.ncbi.nlm.nih | 2.67-fold risk with low 25(OH)D pmc.ncbi.nlm.nih |
| CYP24A1 upregulation | Present in active lesions pubmed.ncbi.nlm.nih | Enhanced vitamin D degradation |
| Overall 25(OH)D deficiency | ~50% of European patients pmc.ncbi.nlm.nih | Worse disease outcomes |
Key Insight
The increased VDR expression in MS is compensatory , not causative. MS patients upregulate VDR expression in an attempt to overcome the upstream metabolic defects in vitamin D activation (CYP27B1), transport (DBP), and excessive degradation (CYP24A1). This explains why MS patients require higher vitamin D doses and why simple supplementation may not fully address the underlying metabolic dysfunction.
The vitamin D metabolism dysfunction in MS is therefore multi-factorial , involving genetic enzyme defects, reduced carrier proteins, enhanced degradation, and compensatory receptor changes - creating a complex web of metabolic inefficiency that contributes to disease pathogenesis and progression.
References
https://jamanetwork.com/journals/jamaneurology/fullarticle/795696
https://jamanetwork.com/journals/jamaneurology/fullarticle/1815002
https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1355916/pdf
https://www.sciencedirect.com/science/article/abs/pii/S0022510X11001080
VitaminDWiki - Genetics has a chart of Vitamin D genes
Vitamin D blood test does NOT notice changes due to 27B1, DBP, and 24A1