Thursday, April 25, 2013

SNPs and their association with the increased risk of developing osteoporosis

Single Nucleotide Polymorphisms (SNPs) are minor changes in the DNA sequence or genetic code of chromosomes. These genetic variances can change the shape and function of protein-containing structures within the body. These structural changes don't always cause problems but in certain cases they can reduce or enhance body functions and have been linked to greater risk in developing chronic diseases like osteoporosis. Being homozygous positive (carrying the same polymorphism on both sets
of genes) for a particular polymorphism doesn't mean that that individual will develop a disease but it only that they may be at greater risk. Knowing if you have certain SNPs can be useful in designing therapeutics protocol. Two specific examples of SNPs related to increased risk for osteoporosis are: 1) vitamin D receptors (VDRs), and 2) IL-1ra, a molecule that helps control chronic inflammation.

Vitamin D Absorption
Vitamin D is known to be of critical importance in the absorption of calcium and phosphate, bone formation, immune regulation, and many other functions of the body. But the key to all that vitamin D you take in from being out in the sun or through your diet or supplements is that it must successfully bind to and stimulate vitamin D receptors (VDRs) on cells in order to be useable. A recent article "Molecular Mechanisms of Vitamin D Action" published in Calcified Tissue International summarizes the vast biological responses that take place when vitamin D binds successfully to its receptor.

Receptors (made up of proteins) are located on or in cells throughout the body and when the proper molecules successfully bind to them, signals for metabolic change take place. For example, when vitamin D successfully binds to a VDR, good things happen. In the gut, VDR stimulation by vitamin D helps improve calcium and phosphate absorption; in osteoblast cells it helps stimulate bone formation; in other parts of the body it helps maintain normal blood cell formation, immune function, kidney regulation of calcium reabsorption, proper balance of the nervous and endocrine systems, and even things like hair growth.

For any molecule (also called a ligand) such as vitamin D to successfully activate its receptor it must  mesh exactly to the surface of its receptor (picture velcro). All the nooks and crannies of each surface have to match perfectly when they come into contact. If not, the ligand/receptor interaction can be foiled by SNPs. If vitamin D can't fit exactly into it's receptor, the person may not be able to efficiently absorb calcium or stimulate osteoblasts to form bone.

If you are homozygous positive for this SNP, one obvious response is to ensure not just an "adequate" vitamin D blood level of 32 ng/ml but a more robust level of 50 to 80 ng/ml. The more vitamin D ligands available, the better the chance of successful attachment to a VDR. Another helpful approach is to use non-vitamin D ligands. Yes, there are molecules other than vitamin D that happen to fit "well enough" into the VDR that they can essentially mimic vitamin D. Two non-vitamin D ligands are docosahexaenoic acid (an omega-3 fatty acid found in cold-water fish) and curcumin, from the spice turmeric

Inflammation Control
Osteoporosis is an inflammation-associated disease process linked to elevated levels of pro-inflammatory cytokines such as interleukin-1 (Il-1), interleukin-6 (Il-6) and tumor necrosis factor (TNF). High levels of Il-1 have been shown to increase bone loss and promote osteoporosis. Interleukin 1-receptor antagonist (Il-1ra) is a competitive inhibitor of Il-1 that occurs naturally in all of us. Its function is to reduce inflammation by jumping on to Il-1 receptors, thereby blocking the pro-inflammatory cytokine Il-1. If the bonding is not successful, the protective effect (reducing inflammation) of Il-1ra will not succeed. When it comes to diseases such as osteoporosis, this ligand/receptor interaction can be foiled by SNPs. This defect in the genetics of Il-1ra will make a person more susceptible to prolonged inflammatory responses which activate osteoclasts and increases their risk for osteoporosis.

If you are homozygous positive for this SNP, one response is to improve the Il-1ra : Il-1 ratio by eating a low-inflammatory diet. This means a diet rich in anti-oxidant packed fruits and vegetables, omega-3 fatty acids from cold-water fish, and botanicals such as milk thistle (silymarin), and curcumin from the spice turmeric. Curcumin is one of the best botanical anti-inflammatory compounds available and has been shown to reduce Il-1 (and Il-6 and TNF).
The Il-1 receptor is similar in shape to another group of receptors called toll-like receptors. This is important because certain white blood cells found in your gut are equipped with these special toll-like receptors that help them find and kill bad bacteria. Because of this similarity between Il-1 receptors and toll-like receptors, if a person has gut bacterial overgrowth AND hyperpermeability (leaky gut syndrome) AND a homozygous SNP for Il-1ra, the adverse effects of inflammation would be greatly compounded.

I happen to be homozygous positive for both VDR and Il-1ra. I also happen to have had about as severe of osteoporosis (T-score -4.3 and 12 fractures in 5 years) as you can get and not break down crying. Do my SNPs have anything to do with my poor bones?...maybe....

Haussler, M.R. et al. 2013. Molecular mechanisms of vitamin D action. Calcified Tissue International 92(2):77-98.
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