Vitamin D is one of the most essential nutrients for human health. It supports bone density, immune function, mood regulation, hormone balance, and even cardiovascular health. But here’s what I’ve learned in clinical practice: some people do everything “right” and are still deficient.
They get sun exposure. They eat well. They supplement. And yet, their labs tell a different story.
Why? Often, the answer lies in their genes.
In this post, I’ll explain how your genetics affect Vitamin D at every stage—from how it’s converted in the liver, to how it’s transported through the bloodstream, to how well it binds to its receptors. Understanding this can help explain stubborn deficiencies and guide more personalized treatment strategies.
Step 1: Conversion – The Role of CYP2R1
When your skin is exposed to sunlight, specifically UVB radiation, your body produces cholecalciferol (vitamin D3). But that’s just the beginning. This raw form must be converted in the liver to 25-hydroxyvitamin D (25(OH)D)—the form measured in blood tests.
This conversion is handled by an enzyme coded by the CYP2R1 gene.
Variants in CYP2R1 can reduce the efficiency of this step, leading to lower circulating levels of 25(OH)D despite adequate sun exposure or supplementation.
(Wang et al., Nature Genetics, 2010)
In practice, I see this with patients who have normal outdoor lifestyles but still show low D levels. Genetic testing often reveals a CYP2R1 polymorphism slowing conversion.
Step 2: Transportation – The GC Gene
Once 25(OH)D is made in the liver, it doesn’t just float freely. It needs a ride through the bloodstream. That ride comes in the form of vitamin D binding protein (DBP), encoded by the GC gene.
Variants in the GC gene can affect:
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How tightly vitamin D binds to DBP
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How much bioavailable vitamin D is present
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How well tissues can access it
Certain GC variants are associated with lower bioavailable D even when total levels appear normal.
(Cheng et al., Journal of Bone and Mineral Research, 2009)
This helps explain why two people with the same serum D level may have very different clinical symptoms.
Step 3: Receptor Binding – VDR Gene
Once transported, vitamin D must bind to the vitamin D receptor (VDR) in target tissues. This is the final and perhaps most important step in how D actually exerts its effects—on gene expression, calcium regulation, immune modulation, and more.
The VDR gene has several common polymorphisms (e.g., Fok1, Bsm1, Taq1) that can affect:
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How strongly D binds to its receptor
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How effectively it activates cellular functions
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How responsive cells are to supplementation
A 2020 review in Frontiers in Immunology confirmed that VDR polymorphisms influence immune function, autoimmune risk, and responsiveness to D therapy.
(Correia et al., 2020)
Clinically, I see this with patients who need higher or more frequent dosing, or who only respond to D3 when paired with cofactors like magnesium and vitamin A.
What You Can Do
If you suspect your body isn’t using vitamin D efficiently, here’s what I recommend:
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Test don’t guess – Ask for 25(OH)D blood levels, and consider testing for vitamin D-related SNPs (CYP2R1, GC, VDR) if you’re consistently low.
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Support cofactors – Vitamin D doesn’t work in isolation. Magnesium, vitamins A and K2, and zinc all support its metabolism and function.
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Use bioavailable forms – Always opt for D3 (cholecalciferol), and consider oil-based delivery or emulsified drops for better absorption.
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Adjust dose based on need – Your genetics may require you to supplement more consistently or at a slightly higher dose than average. Work with a provider to personalize your approach.
Final Thoughts
As a functional medicine provider, I never assume that low vitamin D is just a matter of “not taking enough.” Your genetics shape how your body handles every step of vitamin D metabolism—from skin to cell.
Understanding these pathways helps us go beyond one-size-fits-all medicine and find what really works for your body.
If you’re supplementing and still not feeling a shift—or your labs don’t budge—it might be time to take a closer look at your DNA.