Shining Genetic Light on Your Vitamin D Levels

Vitamin D is essential to many processes in the body. It isn’t actually a vitamin at all, but a prohormone that is synthesized in the skin when exposed to UV radiation.

Genes play a big role in your body’s susceptibility to low vitamin D levels. Read on to learn how to check your 23andMe results for your vitamin D genes and find solutions tailored to your specific genetic variants.

Vitamin D: What does it do for you?

Low Vitamin D levels are linked to a variety of chronic conditions, from mood disorders to cancer risk to immunity to bone density. In general, higher vitamin D levels correspond to a lower risk of getting a variety of chronic diseases.

People think of vitamin D in regards to bone health because it regulates the uptake of calcium to keep bones strong. But there is a lot more to vitamin D and your health. It acts in your cells to regulate the production of hundreds of different enzymes, influencing wellness in a multitude of ways.

How do you produce vitamin D?

Vitamin D is produced in the skin from exposure to sunlight. It is produced via a reaction with UVB radiation and cholesterol in the skin.[ref]

The initial form of vitamin D formed in the skin (or taken as a supplement) is the inactive form (cholecalciferol). It must goes through a couple of steps to convert it into the active form.

  • First, it can be converted in the liver into 25-hydroxy vitamin D  – 25(OH)D – with the help of an enzyme coded for by the CYP2R1 gene.
  • That 25(OH)D then needs to go through one more step to be the active form that your cells need. To convert the 25(OH)D  into the active form – 1,25(OH)2D3  or calcitriol,  cells use an enzyme that is encoded by the CYP27B1 gene.

Your body’s 25(OH)D levels are essentially dependent on how much you take in from food and sunlight.

The 1,25(OH)2D3 (calcitriol) levels are more tightly regulated, and the active form is converted when and where it is needed within the cells.

What exactly does vitamin D do?

In a nutshell, vitamin D can cause cells to turn on genes, making certain proteins needed in a cell.

To get a little more specific…
Inside of your cells, vitamin D binds to the vitamin D receptor  (VDR).  This then causes VDR to get together with a couple of other proteins (one is a vitamin A-related receptor) and bind to different spots on the nuclear DNA. This activates the transcription of certain genes. In fact, vitamin D controls the expression of about 3% of the human genome. So, yeah, it’s pretty important.

Additionally, vitamin D can act as a hormone within cells to immediately cause non-DNA related actions to take place – such as opening ion channels or causing the secretion of insulin.

The term pleiotropy gets used a lot in research papers about vitamin D. Pleiotropy just means that one gene (or in this case one product of a gene, calcitriol) can cause more than one completely different action or trait to occur.  In other words, vitamin D does a lot of stuff in the body that is seemingly unrelated. For example, Vitamin D is essential for calcium regulation and strong bones — and vitamin D is also essential for immune response. It is also important in cancer prevention, hypertension, atrial fibrillation, blood clots, inflammatory bowel disease, and autoimmune disease. [ref]

For Vitamin D to be used in the nucleus of cells, it needs to be transported there by a binding protein that is coded for by the GC gene, and then it needs to bind to the vitamin D receptor, which is coded for by the VDR gene.

Does supplementing with vitamin D actually do anything?

While low levels of vitamin D have been associated with a higher risk of a bunch of chronic conditions, supplementing with vitamin D doesn’t always give impressive results in placebo-controlled studies. For example, a recent clinical trial found little benefit for postmenopausal women when looking at bone mineral density. On the other hand, the amount of vitamin D used in the trial may have been too small to get a result.[ref]

One reason that some of the research studies and clinical trials of vitamin D supplementation showed no positive results is because the doses used may have been too low.

A study came out a couple of years ago claiming there was a statistical error in the calculation for the recommended daily intake of vitamin D.[ref] This error changed the supplemental doses needed by a factor of 10.  Instead of 600 IU, some people may need 6,000IU+ per day. Other recent studies have backed this up, showing also that a person’s weight plays a big role in the amount of vitamin D needed for sufficiency.

A recent meta-analysis combining data from 52 different trials found that vitamin D supplementation did not impact overall mortality rates, but it did decrease the risk of death from cancer.


Vitamin D Genetic Variants:

Genetics can play a role in vitamin D levels in several ways, which makes sense when looking at the different steps involved in converting it to the active form which then acts on the vitamin D receptors in a cell.

Below are genetic variants that have been shown in multiple research studies to impact vitamin D levels.

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GC Gene:

The vitamin D binding protein is coded for by the GC gene, and variants in the gene affect the total serum levels of 25(OH)D. The frequency of the variants in the GC gene vary in different population groups, and this is thought to be a big part of the difference in vitamin D levels among populations.

Check your genetic data for rs2282679 (23andMe v4, v5; AncestryDNA):

  • T/T: typical vitamin D levels[ref]
  • G/T: somewhat lower total serum vitamin D levels
  • G/G: lower serum vitamin D levels[ref][ref]

Members: Your genotype for rs2282679 is .

Check your genetic data for rs7041 (23andMe v.4, v.5; AncestryDNA):

  • C/C: typical Vitamin D levels[ref]
  • A/C: somewhat lower vitamin D levels[ref]
  • A/A: lower Vitamin D levels[ref][ref]

Members: Your genotype for rs7041 is .

Check your genetic data for rs12512631 (23andMe v4; AncestryDNA):

  • T/T: typical vitamin D
  • C/T: typical vitamin D
  • C/C: increased vitamin D (both 25 and 1,25) levels.[ref]

Members: Your genotype for rs12512631 is .

Check your genetic data for rs1155563 (23andMe v4, v5; AncestryDNA):

  • T/T: typical vitamin D
  • C/T: lower vitamin D
  • C/C: significantly lower vitamin D levels[ref][ref]

Members: Your genotype for rs1155563 is .

VDR Gene: vitamin D receptor

After vitamin D (from sunlight, food, or supplements) has gone through the conversion steps, the active form, calcitriol, can act on cells through the vitamin D receptor (VDR) which is a transcription factor that turns a gene on or off.  Vitamin D receptors control a variety of different functions including the activity of the immune system, skin, pancreas, and bone tissue. There have been many studies on these VDR gene variants, with some studies showing conflicting results. Note that there are popular websites online with reports on the VDR gene that are basing their + or – information on just a few older studies.[ref]

Check your genetic data for rs731236 (23andMe v.4, v.5; AncestryDNA):

  • G/G: typical[ref]
  • A/G: one copy of VDR Taql
  • A/A: VDR TaqI variant[ref]

Members: Your genotype for rs731236 is .

Check your genetic data for rs1544410 (23andMe v4, v5; AncestryDNA):

  • C/C: typical bone mineral density[ref]
  • T/T: carrier of BsmI variant, possible increased risk of low bone mineral density[ref][ref]

Members: Your genotype for rs1544410 is .

Check your genetic data for rs2228570 (23andMe v4 only):

  • A/A: typical
  • A/G: typical vitamin D levels[ref]
  • G/G: carrier of FokI variants, possibly decreased vitamin D levels, pos. increased risk of fractures[ref][ref][ref] increased risk of tuberculosis[ref]

Members: Your genotype for rs2228570 is .

Check your genetic data for rs7975232 (23andMe v4, v5; AncestryDNA)

  • C/C: half the risk of dengue fever[ref]
  • A/C: typical risk of dengue fever
  • A/A: typical risk of dengue fever

Members: Your genotype for rs7975232 is .

Check your genetic data for rs10783219 ( AncestryDNA)

  • A/A: typical
  • A/T: lower vitamin D levels, even with supplementation
  • T/T: lower vitamin D levels, even with supplementation[ref]

Members: Your genotype for rs10783219 is .

CYP2R1 Gene:

CYP2R1 is the gene that codes for the enzyme that converts D3 into 25-hydroxyvitamin D (25(OH)D).

Check your genetic data for rs2060793 (23andMe v4, v5; AncestryDNA):

  • A/A: lower vitamin D levels[ref]
  • A/G: typical vitamin D levels
  • G/G: higher vitamin D levels

Members: Your genotype for rs2060793 is .

Check your genetic data for rs1562902 (23andMe v4, v5; AncestryDNA):

  • T/T: higher vitamin D levels[ref]
  • C/T: typical vitamin D
  • C/C: typical vitamin D levels

Members: Your genotype for rs1562902 is .


CYP27B1 Gene:

The second step in the conversion to the active form of vitamin D involves CYP27B1 as a catalyst for the conversion of 25(OH)D into 1,25(OH)D. This takes place mostly in the kidneys or immune system cells. A couple of rare mutations (listed below) of CYP27B1 do affect the conversion to the active form of vitamin D, and these mutations are linked to rickets, a disease caused by the lack of vitamin D in childhood.

Check your genetic data for rs28934607 (23andMe v4; AncestryDNA):

  • A/A: pathogenic for Vitamin D related rickets[ClinVar]
  • A/G: carrier of a pathogenic allele
  • G/G: typical

Members: Your genotype for rs28934607 is .

Check your genetic data for rs28934605 (23andMe v4; AncestryDNA):

  • T/T: pathogenic for Vitamin D related rickets[ClinVar]
  • C/T: carrier of a pathogenic allele
  • C/C: typical

Members: Your genotype for rs28934605 is .

Check your genetic data for rs28934604 (23andMe v4; AncestryDNA):

  • T/T: pathogenic for Vitamin D related rickets[ClinVar]
  • C/T: carrier of a pathogenic allele
  • C/C: typical

Members: Your genotype for rs28934604 is .

VDBP gene:


Lifehacks:

Circadian Rhythm, Melatonin, and preventing damage from sun exposure:

Our skin naturally makes vitamin D through exposure to the sun. However, sun exposure seems to be a double-edged sword these days, with UV light giving us vitamin D as well as increasing our risk for cancer. It makes you wonder why all of our ancestors didn’t end up with skin cancer without a handy bottle of sunscreen available.

Turns out that our modern lifestyle with light at night (TVs, tablets, phones, and LED light bulbs) has decreased our melatonin production. Melatonin at the right time plays a big role in both our circadian rhythm and our skin’s natural ability to withstand UV rays without creating skin cancer. Blocking blue light wavelengths at night increases melatonin production and should increase our skin’s ability to utilize UV rays for vitamin D production without the harmful effects.[ref]  Read more about melatonin production, genetics, and blue light.

In addition to light at night, the time at which you eat also influences the circadian rhythm of your genes. A recent study showed mice eating at the wrong time (equivalent to humans eating at night) had increased skin damage from UV light.[ref] Basically, eating at the wrong time-shifted the phase of the circadian rhythm of skin genes to where UV damage would be less of a problem at night rather than during the day… and the sun doesn’t shine at night! So an easy ‘lifehack’ here would be to eat dinner earlier in the evening and don’t snack at night.

Food and Supplements:

Currently, the US and Canada add vitamin D to milk. Fatty fish, such as salmon, tuna, and mackerel, are also good sources of vitamin D. Some types of mushrooms, when exposed to UV light, also contain vitamin D (as D2).

There are many vitamin D supplements available at stores and online. Keep in mind, vitamin D is fat-soluble and supplements usually contain oil such as soybean oil, which you may want to avoid. Again, the jury seems to still be out when it comes to a definitive recommendation on how much vitamin D is needed; you may find that your sun exposure is enough to keep your levels high enough.

Gut Microbiome:

The VDR gene, as well as other genes associated with vitamin D, plays a role in gut microbiome diversity. VDR knockout mice had a 42% decrease in the microbiome diversity index. That is pretty huge. Parabacteroides is one of the taxa that is affected by VDR genetic variants; it feeds on resistant starch, so adding in fiber and resistant starch might help encourage that microbe if you have decreased VDR.[ref]

Testing Vitamin D levels:

If you haven’t recently tested your vitamin D level, it is an easy and fairly inexpensive blood test.  If you are in the US, there are lots of online sites where you can order lab tests without doctor’s orders, such as UltaLabs.


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Circadian Rhythms: Genes at the Core of Our Internal Clocks
Circadian rhythms are the natural biological rhythms that shape our biology.  Most people know about the master clock in our brain that keeps us on a wake-sleep cycle over 24 hours.  This is driven by our master ‘clock’ genes. It turns out that we also have circadian cycles (peripheral clocks) in most organs such as the liver, pancreas, and fat cells. These peripheral rhythms drive the cyclical production of proteins in our organs.

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.