How Your Genes Influence Vitamin D’s Impact on Multiple Sclerosis

Vitamin D is much more than the “sunshine vitamin.” Beyond its role in bone health, it plays a key part in immune regulation — making it a molecule of great interest in autoimmune diseases like multiple sclerosis (MS).

People with low vitamin D levels have consistently shown a higher risk of developing MS and often experience worse disease activity once diagnosed. This has led many researchers and clinicians to explore whether vitamin D supplementation could help slow down disease progression or reduce relapses.

However, the results of vitamin D supplementation studies in MS have been mixed. Some show no measurable benefit, while others suggest improvements in relapse rates or MRI activity. So, what could explain this inconsistency?

One answer may lie in our genes.

Genetic Polymorphisms: The Missing Piece?
The study by Mimpen and colleagues from Maastricht University and Erasmus MC explored whether genetic differences in vitamin D metabolism could explain why some MS patients respond better to vitamin D supplements than others.

Specifically, they looked at single nucleotide polymorphisms (SNPs) — small variations in DNA that can affect how proteins function. Four SNPs were selected, each involved in vitamin D transport or metabolism:

rs4588 and rs7041 – variants in the vitamin D-binding protein (DBP) gene, which helps carry vitamin D in the blood.

rs12368653 – located near the CYP27B1 gene, which converts vitamin D into its active form.

rs2248359 – near the CYP24A1 gene, which breaks down active vitamin D.

Some of these SNPs are also known to be MS risk alleles, suggesting that vitamin D-related genetic variation might play a dual role — influencing both disease susceptibility and treatment response.

The SOLARIUM Study: Testing the Hypothesis
This genetic analysis was a follow-up to the SOLARIUM trial, itself a sub-study of the larger SOLAR trial, which evaluated high-dose vitamin D3 supplementation in relapsing-remitting MS (RRMS) patients already receiving interferon-β therapy.

In SOLARIUM, participants were randomized to receive either a placebo or 14,000 IU of vitamin D3 daily for nearly a year (48 weeks).

From this cohort, 34 participants consented to genetic testing, and 26 had complete vitamin D data available. The researchers compared how 25-hydroxyvitamin D [25(OH)D] levels — the main circulating form of vitamin D — changed after supplementation in “carriers” versus “non-carriers” of the risk alleles.

Key Findings: Genes Shape the Response
The results revealed two key genetic effects:

1. DBP Gene Variant (rs7041)
At baseline, carriers and non-carriers had similar vitamin D levels.

After 48 weeks of supplementation, carriers of the rs7041 risk allele had significantly lower 25(OH)D levels than non-carriers.

Median 25(OH)D: 224.2 nmol/L (carriers) vs. 332.0 nmol/L (non-carriers)

p = 0.013

This suggests that people with this variant may not absorb or retain vitamin D as efficiently, even when taking high doses.

2. CYP27B1 Variant (rs12368653)
Again, no baseline difference was observed.

After supplementation, carriers of the rs12368653 risk allele actually had higher 25(OH)D levels compared to non-carriers.

Median 25(OH)D: 304.1 nmol/L vs. 152.0 nmol/L

p = 0.014

This could indicate a more efficient conversion or regulation of vitamin D metabolism among carriers, though the mechanism remains speculative.
3. Other Variants (rs4588 and rs2248359)
No significant differences were observed for these SNPs, though prior studies have linked them to vitamin D status in larger populations. The small sample size here may have limited statistical power.

What Does This Mean?
These findings highlight that vitamin D supplementation is not “one-size-fits-all.” Genetic differences can significantly alter how the body processes vitamin D, even when doses are extremely high.

For example:


Someone with the rs7041 variant might need more vitamin D to achieve the same serum levels as others.

Conversely, carriers of rs12368653 may respond more strongly, potentially requiring lower doses to avoid excessive levels.

This genetic influence could help explain why clinical trials on vitamin D in MS have yielded inconsistent results — participants’ genetic backgrounds weren’t always accounted for.

Limitations and Next Steps
The study was small (only 26 participants with complete data), meaning the results should be interpreted cautiously. It also focused on very high-dose supplementation, producing vitamin D levels above the physiological range. Whether similar effects occur at typical daily doses (e.g., 1,000–4,000 IU) remains to be tested.

Future research should:

Examine larger, genetically diverse cohorts,

Assess clinical outcomes (not just vitamin D levels), and

Explore whether genetic screening could guide personalized vitamin D therapy in MS.

Conclusion: Toward Personalized Vitamin D Therapy
This study adds a valuable piece to the complex puzzle of vitamin D and multiple sclerosis. It suggests that our genes can influence how our bodies respond to supplementation, potentially explaining why some people benefit while others don’t.

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:
Mimpen, M., Rolf, L., Poelmans, G., van den Ouweland, J., Hupperts, R., Damoiseaux, J., & Smolders, J. (2021). Vitamin D related genetic polymorphisms affect serological response to high-dose vitamin D supplementation in multiple sclerosis. PLoS One, 16(12), e0261097.