Trait: Vitamin D Level (GC)
Dr Haran Sivapalan
October 4, 2020
What is Vitamin D?
Vitamin D is a fat-soluble vitamin that plays an important role in maintaining levels of calcium and phosphate in the body. This helps us to build and maintain strong and healthy bones.
Vitamin D is also important for immune function, glucose metabolism, and maintaining good cardiovascular health.
You may have heard of Vitamin D referred to as the “sunshine vitamin.” This is because our skin produces Vitamin D when exposed to UV rays in sunlight. Vitamin D is also present in various foods (e.g. oily fish, dairy products, fortified cereals) and supplements.
- Vitamin D is fat-soluble vitamin important for bone health, immune function, glucose metabolism and cardiovascular health.
- Our skin produces Vitamin D in response to sunlight.
Why is Vitamin D important?
Regulation of calcium levels and maintaining bone health
Our body tightly controls calcium levels in the bloodstream. Regulating calcium levels within a narrow range is necessary for effective nerve and muscle function, sustaining bone mineral density, and promoting bone growth. (You can read more about the importance of calcium in your Blood Calcium Level trait).
Vitamin D helps to maintain healthy blood calcium levels in three principal ways:
- It promotes the absorption of dietary calcium in the intestines.
- It promotes the reabsorption of calcium into the bloodstream by the kidneys.
- It frees calcium from bone when blood calcium levels are low.
Vitamin D also helps to main healthy phosphate levels. Phosphate is a form of the mineral phosphorus and, like calcium, plays a role in bone health and nerve and muscle function. The regulation of phosphate levels in the body is closely tied to the regulation of calcium levels, with Vitamin D helping to increase absorption of phosphate in the intestine.
By helping to maintain adequate calcium and phosphate levels in the bloodstream, Vitamin D supports bone health. By contrast, Vitamin D deficiency can lead to a loss of bone mineral density and the development of osteoporosis in adults, whereby bones become fragile and more susceptible to fracture.
Vitamin D plays an important role in our immune response.
As described in our How do I boost my immune system? article, Vitamin D stimulates certain components of our innate immune system. Our innate immune system is the fast-acting, non-specific strand of our immune system that includes physical barriers such as skin, the acute inflammatory response, and various white blood cells.
Vitamin D is thought stimulate white blood cells called macrophages to engulf pathogens (disease-causing agents such as bacteria, viruses, fungi). Vitamin D also stimulates macrophages to secrete specialized antimicrobial substances that neutralise bacteria.
By contrast, our acquired immune system may be suppressed by Vitamin D. The acquired immune system is the slow-acting, specific strand of our immune response that is targeted to particular pathogens. The main components of our acquired immune system include B-cells, which produce antibodies that are targeted to specific pathogens, and T-cells, which destroy infected cells or secrete chemicals called cytokines to recruit other immune cells and coordinate an immune response.
Vitamin D is thought to suppress the production of antibodies by B-cells (labelled CD19 on the above diagram) and also inhibit the proliferation of T-cells (e.g. Th1 on the above diagram). It is thought that this suppressive effect could actually be beneficial, as it may help to prevent autoimmunity – whereby the immune system attacks our own healthy cells.
Insulin is a key hormone that allows cells to take up and use glucose from the bloodstream.
Vitamin D is thought to play a role in both the secretion of insulin and tissue sensitivity to insulin. For example, studies suggest that Vitamin D improves insulin sensitivity by causing muscle cells to express more insulin receptors.
By contrast, low Vitamin D levels have been linked to higher blood glucose levels and an increased risk of Type II diabetes.
Control of blood pressure
Vitamin D influences the activity of the Renin-Angiotensin-Aldosterone System. This a system of hormones that regulates blood pressure and blood volume.
On this note, some observational studies have demonstrated a link between low Vitamin D levels and high blood pressure, although the exact relationship is unclear.
- Vitamin D helps to maintain healthy calcium and phosphate levels required for bone development and maintenance of bone mineral density.
- Vitamin D stimulates the innate immune system to fight off infection while suppresses some parts of the acquired immune system. This may help prevent the immune system from damaging healthy cells.
- Vitamin D helps to maintain healthy blood sugar levels by improving the secretion of- and sensitivity to insulin.
- Vitamin D helps to regulate blood pressure by reducing the activity of the Renin-Angiotensin-Aldosterone system.
What are the different forms of Vitamin D?
There are two main forms Vitamin D:
- Vitamin D2 (ergocalciferol)
- Vitamin D3 (cholecalciferol)
Vitamin D2 is the form of Vitamin D found in plants and mushrooms, various fortified foods (e.g. breakfast cereals), and some supplements.
Vitamin D3 is the form of Vitamin D produced by our skin on exposure to sunlight. It is also found in animal sources, including oily fish (e.g. salmon, mackerel, sardines), fish oils (e.g. cod liver oil), eggs; certain fortified foods (e.g. milk); and some supplements.
Active forms of Vitamin D
Neither Vitamin D2 nor D3 are biologically active in the body. They must first be converted into the active form of Vitamin D: 1,25 dihydroxy-vitamin D (also known as calcitriol). This molecule is also denoted as: 1,25(OH)2D.
The conversion of inactive into active Vitamin D takes place in two stages. In the liver, Vitamin D3 and D2 are first converted into 25-hydroxy-vitamin D (also known as calcidiol). This molecule is also denoted: 25(OH)D and is the main form of Vitamin D circulating in the bloodstream.
In the second stage of conversion, the kidney converts 25-hydroxy Vitamin D into the active 1,25-dihydroxy-vitamin D (also known as 1,25(OH)2D or calcitriol). This active form of Vitamin D also circulates in the bloodstream.
Once produced by the kidney, 1,25(OH)2D acts as a hormone: a chemical messenger that affects the function of other cells. Nearly all cells in the body have a receptor for 1,25(OH)2D, known as the Vitamin D receptor (VDR).
When 1,25(OH)2D binds to VDR, it causes cells to switch on certain genes, while switching others off. These changes (known as changes in gene expression) are responsible for many of Vitamin D’s effects in the body.
Which is better – Vitamin D2 or D3?
Blood levels of 25-hydroxy-vitamin D (or 25[OH]D) are a good measure of your body’s overall levels of Vitamin D.
Studies suggest that while both Vitamin D2 and Vitamin D3 supplements increase blood 25(OH)D levels, Vitamin D3 is more effective than D2.
Therefore, if you’re thinking of taking Vitamin D supplements, it may be better to opt for those containing Vitamin D3.
- The two major forms of Vitamin D are D2 and D3.
- D3 is produced by our skin on exposure to sunlight.
- D3 is also found in foods such as fish, eggs, and dairy products.
- D2 is found in plant-based foods and mushrooms.
- 1,25 dihydroxy-vitamin D (1,25[OH]2D) is the active form of Vitamin D in the body.
- Both D2 and D3 must be converted into the active 1,25(OH)2D to have effects in the body.
- The liver first converts D2 and D3 into 25-hydroxy-Vitamin D (25[OH]D).
- The kidneys then convert 25(OH)D into 1,25(OH)2D: the active form of Vitamin D.
- Levels of 25(OH)D in the bloodstream is a commonly used as a measure of Vitamin D status.
- D3 is more effective than D2 at increasing 25(OH)D levels.
What is a healthy Vitamin D level?
The blood serum concentration of total 25(OH)D (25 hydroxy-vitamin D) is the most commonly used measure of someone’s Vitamin D level. It reflects the amount of Vitamin D both produced by the skin and obtained from the diet (including supplements).
You may be asking why levels of 25(OH)D and not 1,25(OH)2D, the active form of Vitamin D, are used to assess Vitamin D levels. The reasons for this are because 25(OH)D has a longer half-life in the bloodstream and its levels vary more reliably with changes in Vitamin D intake.
Healthy Vitamin D level ranges
According to the Institute of Medicine, a healthy serum total 25(OH)D level is between 50 nmol/L (20 ng/ml) and 125 nmol/L (50 ng/ml).
There is still some debate over where the cut-off for low Vitamin D levels should be. The Endocrine Society recommend that people should aim for serum total 25(OH)D level above 75nmol/L (30 ng/ml) to maximise bone health and muscle function.
Low Vitamin D levels
Sub-optimal Vitamin D levels can be classified (according to the Institute of Medicine criteria) as:
- Vitamin D insufficiency – serum total 25(OH)D between 30 and 50 nmol/L (12 – 20 ng/ml)
- Vitamin D deficiency – serum total 25(OH)D less than 30 nmol/L (12 ng/ml).
- Serum total 25(OH)D is used to measure Vitamin D levels.
- Healthy levels are in the range: 50 – 125 nmol/L (20 – 50 ng/ml).
- Some experts suggest a higher minimum level of 75 nmol/L (30 ng/ml) for healthy bone and muscle function.
How is Vitamin D transported in the bloodstream?
As explained earlier, Vitamin D obtained from our diet or made by our skin undergoes a process of conversion into 25-hydroxy-vitamin D (25[OH]D) and then into the active form of Vitamin D: 1,25-dihydroxy-vitamin D (1,25(OH)2D).
The vast majority (≈ 85%) of both 25(OH)D and 1,25(OH)2D is transported in the bloodstream bound to a specialized carrier protein known as Vitamin D binding protein (DBP).
Cells in some tissues, such as the kidney, have specialized receptors which bind to DBP in the bloodstream and allow 25(OH)D and 1,25(OH)2D to enter cells.
Roughly 15% of 25(OH) D and 1,25(OH)2D is bound to another carrier protein in the blood: albumin.
Only 0.03% of 25(OH)D and 0.4% of 1,25(OH)2D is unbound and free. In most tissues, it is thought that only free 25(OH)D and 1,25(OH)2D can enter cells and exert biological effects.
Most blood tests for Vitamin D levels measure total 25(OH)D. This includes the amount of 25(OH)D (25-hydroxy-vitamin D) that is bound to DBP and albumin, as well as free 25(OH)D.
- Vitamin D (including D2, D3, 25[OH]D and 1,25[OH]2D) is transported in the bloodstream bound to a carrier protein called Vitamin D binding protein (DBP).
- The vast majority of 25(OH)D and 1,25(OH)2D in the bloodstream is bound to DBP.
- It is thought that for most tissues, only free, unbound 25(OH)D and 1,25(OH)2D can enter cells and exert effects.
- Blood vitamin D levels typically measure serum total 25(OH)D – this includes 25(OH)D bound to DBP and albumin, and free, unbound 25(OH)D.
What is the GC gene?
Your GC gene codes for Vitamin D binding protein (DBP).
Studies suggest that variants of your GC gene can affect the ability of DBP to bind to 25(OH)D and 1,25(OH)2D. Furthermore, different GC gene variants may alter the amount of DBP produced by the body.
As a result of these effects, different GC gene variants have been associated with differences in Vitamin D levels.
- Vitamin B binding protein (DBP) is encoded by your GC gene.
- GC gene variants can influence your Vitamin D levels.
What are the different GC gene variants?
The most common source of genetic variation in humans are SNPs (Single Nucleotide Polymorphisms). SNPs are single-letter changes in our DNA code. These single-letter changes give rise to different gene variants, which we call “alleles”.
There are two common SNPs within the GC gene:
- rs7041 – which causes a change in the DNA code from the letter ‘T’ to ‘G’.
- rs4588 – which causes a change in the DNA code from the letter ‘C’ to ‘A’.
These two SNPs give rise to three different GC gene variants / alleles:
- 1f – which has the ‘T’ from rs7041 and the ‘C’ from rs4588.
- 1s – which has the ‘G’ from rs7041 and the ‘C’ from rs4588.
- 2 – which has the ‘G’ from rs7041 and the ‘A’ from rs4588.
Due to differences in their DNA code, the three different alleles (Gc1f, 1s and 2) code for slightly different forms of the Vitamin D binding (DBP) proteins. In particular, the various DBP forms may differ in their ‘binding affinity’ – which is a measure of the strength to which DBP binds 25(OH)D and 1,25(OH)D2.
Although findings vary, some studies suggest that DBP encoded by the Gc1f allele has the highest binding affinity for 25(OH)D and 1,25(OH)D2, whereas the Gc2 allele is associated with the lowest binding affinity.
The different alleles have also been linked to differences in the amount of DBP produced and circulating in the bloodstream. Several studies have found that the Gc2 allele is associated with lower circulating levels of DBP.
Given these effects, your Vitamin D levels (as measured by total 25[OH]D) depend partly on what particular GC alleles you inherit.
- There are three different variants (alleles) of the GC gene: 1f, 1s, and 2.
- The 1f, 1s, and 2 variants each code for slightly different forms of Vitamin D binding protein (DBP).
- The different GC gene variants affect Vitamin D (serum total 25[OH]D) levels.
What are the different GC genotypes?
We inherit genes in pairs, one from our mother and the other from our father. Given there are 3 different variants or ‘alleles’ of the GC gene (1f, 1s, and 2), we can have one of six possible GC gene combinations (or genotypes):
- 1f / 1f
- 1f / 1s (may also be denoted 1s / 1f)
- 1f / 2
- 1s / 1s
- 1s / 2
- 2 / 2
The different GC genotypes affect the form of Vitamin D Binding Protein (DBP) that you produce. Moreover, studies suggest the six different genotypes are associated with slight differences in Vitamin D levels.
Your Vitamin D Levels (GC) Trait will inform you of your specific GC genotype and predicted Vitamin D (25[OH]D) Level.
- You can have one of six possible GC genotypes: 1f/1f, 1f/1s, 1f/2, 1s/1s, 1s/2, and 2/2.
- Different GC genotypes are associated with differences in Vitamin D levels.
How do the different GC genotypes affect Vitamin D levels?
As explained earlier, the most commonly used measure of Vitamin D level is serum total 25(OH)D (also known as 25-hydroxy-vitamin D).
Several studies have reported differences in serum total 25(OH)D across the six GC genotypes. While the exact results vary from study to study, there is a common finding that people with the 2/2 genotype tend to have lower 25(OH)D levels compared to other genotypes.
For example, a large Norwegian study of 11,704 subjects, known as the Tromso study, found that those with the 2/2 genotype had an average 25(OH)D level of 46.9 nmol/L.
By contrast, those with other genotypes had average 25(OH)D levels ranging from 50.3 to 55.4 nmol/L.
To put these figures in context, a healthy Vitamin D (25[OH]D) level is considered to be between 50 and 125 nmol/L.
Studies in several other populations, including Han Chinese, west African and northern European subjects, show a similar pattern: individuals with the 2/2 GC genotype have significantly lower Vitamin D levels.
The graph below, taken from the MARIE study based in Germany, illustrates this pattern.
These results suggest that individuals with the 2/2 genotype are at greater risk of low Vitamin D levels (i.e. Vitamin D insufficiency and deficiency).
On the plus side, people with 2/2 genotype have been shown to respond more favourably to long term Vitamin D supplementation. For example, one study found that the 2/2 genotype produced much greater increases in serum 25(OH)D levels after taking either 600IU or 4000IU of Vitamin D3 supplements daily over the course of a year.
- Studies show that individuals with the 2/2 GC genotype have lower Vitamin D levels compared to other genotypes.
- People with the 2/2 genotype may be a greater risk of Vitamin D insufficiency and deficiency.
- Some studies suggest that people with the 2/2 genotype show greater increases in Vitamin D levels in response to taking Vitamin D supplements.
Why is the 2/2 genotype associated with lower Vitamin D (25[OH]D) levels?
It’s unclear why exactly people with the 2/2 GC genotype have lower Vitamin D levels.
We know that the Gc2 allele may code for a Vitamin D binding protein (DBP) with a lower binding affinity for 25(OH)D. However, we also know that it is free, unbound 25(OH)D that is active in the body.
Given these two findings, we might expect people with the 2/2 genotype to have higher levels of free 25(OH)D (as they produce a DBP protein which binds less Vitamin D). Studies suggest this is not the case, with people with the 2/2 genotype actually shown to have lower levels of free 25(OH)D.
Another potential explanation is that people with the 2/2 genotype produce lower quantities of DBP.
Some studies which have directly measured levels of DBP in the bloodstream have found that those with the 2/2 GC genotype do in fact have lower levels of circulating DBP. Given that the majority of 25(OH)D circulating in the bloodstream is bound to DBP, lower DBP levels may explain the finding of lower serum total 25(OH)D levels in the 2/2 genotype.
- Studies suggest that the people with the 2/2 GC genotype have lower levels of free 25(OH)D.
- Studies show the 2/2 genotype is linked to lower circulating levels of DBP.
Your Vitamin D Level (GC) trait
Your Vitamin D Level (GC) Trait tells you your particular GC genotype and uses this genetic data to predict your Vitamin D levels. You will fall into one of the six possible categories:
- Average Vitamin D levels – 1f/1f, 1f/1s, 1f/2, 1s/1s, 1s/2 genotypes
- Low Vitamin D levels – 2/2 genotype
To view your trait results, please login to Truefeed.