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Relationship between D and single nucleotide polymorphisms

Posted on: November 4, 2011   by  John Cannell, MD

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Professor Martin Hewison of the David Geffen School of Medicine at UCLA is one of the giants in the field of vitamin D research. His October 2011 review of vitamin D’s role in immunity is exhaustive and thought provoking. Vitamin D’s role in all forms of immunity seem so important that it is amazing that vitamin D deficient people can stay alive very long.

Hewison M. An update on vitamin D and human immunity. Clin Endocrinol (Oxf). 2011 Oct 13. doi: 10.1111/j.1365-2265.2011.04261.x. [Epub ahead of print]

However, Professor Hewison wandered a bit and reviewed the many ways that genetics are involved in your vitamin D system. It turns out that genetic variations, called single nucleotide polymorphisms (SNPs), are common in just about every protein involved with vitamin D, including the vitamin D receptor, the enzyme that makes activated vitamin D and the protein that transports vitamin D in the blood.

No one really knows what all these SNPs mean, although a recent study looking at different SNPs in the vitamin D binding protein found that the binding protein that lets go of the most 25(OH)D (low affinity) showed better antibacterial responses than the high affinity binding protein. What percentages of people have high affinity binding proteins or low affinity ones appear to be unknown, although the same kind of genetic variation in the receptor protein is widespread. Furthermore, scientists have studied the SNPs in the receptor protein for years with very conflicting results.

I suspect that when they study SNPs in the binding proteins and the activating proteins intensely, scientists will again confront conflicting results.These small mutations are incredibly common, so common that at times it is hard to know which ones are “normal.” The normal one may be the one that works the best at what it is supposed to do, although this is far from certain as well. Say these mutations are nature’s evolutionary way of improving the system; it may be that one relatively recent SNP (in evolutionary time) is better at what it does than the “normal” one.

One thing that has arisen from this research is the concept of “free” vitamin D or more accurately “free 25(OH)D.” At any given 25(OH)D level, as some people have low affinity vitamin D binding proteins, those proteins will find it easier to shed 25(OH)D and those people will have higher levels of free 25(OH)D in their blood. People with high affinity binding protein will have more of their 25(OH)D bound to the protein and thus have lower free 25(OH)D levels. In fact a recent study showed free 25(OH)D was better correlated with bone mineral density than was total 25(OH)D.

So say you have SNPs that leave you with the least effective receptor, the least efficient activating enzyme and the high affinity binding protein, and many people do, where does that leave you? I’m not sure, but since all of these SNPs are functional, it seems to me that if you have bad genetic luck, you want to be sure you’re sufficient in vitamin D.

2 Responses to Relationship between D and single nucleotide polymorphisms

  1. rghammonds

    Understanding the effects of vitamin D may be complicated by genetic differences unrelated to the enzymes, transporters, and receptors that interact directly with vitamin D.
    The recent study on COPD and vitamin D is a good example. Genotyping SNPs associated with COPD (*) might have allowed detection of significant effects of vitamin D in subgroups.
    * http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000421

  2. JBG

    The relation between 25(OH)D and its binding protein appears analogous with the relation between, eg, testosterone and sex hormone binding globulin. If that’s so, then a test for the 25(OH)D binding protein might help a lot to sort out variation in the effect of different levels of 25(OH)D in different people. Testosterone that is bound to SHBG is effectively out of the game. It’s the free/bioavailable testosterone that does the work. It would be useful to know if something like the same holds for 25(OH)D.

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