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Genes affect vitamin D processing in many places - 2010

Genetics of vitamin D metabolism

Dr David S Grimes MD FRCP, Consultant Physician, Royal Blackburn Hospital

It is now clear and increasingly appreciated that vitamin D has an important role in cellular processes other than bone formation. Furthermore, many observations show that low levels of vitamin D in the blood are associated with a variety of disease states and also a relatively short lifespan. The diseases identified include multiple sclerosis, coronary heart disease, chronic obstructive pulmonary disease, and a number of cancers including lung, breast, prostate, pancreas, oesophagus and colon. There is some scepticism as to how one substance such as vitamin D can have such wide-ranging effects. What is not generally appreciated is that vitamin D is simply a pro- hormone and it is the activation of vitamin D receptors (VDR’s) within the cells that produces a wide range of intra-cellular effects. Perhaps the most important is that vitamin D responsive elements (VDRE) within cells have a controlling effect on more than 1000 genes.

It has also been noted that there is a wide variation of blood levels of vitamin D measured as 25 (OH)D among people who might take similar amounts of vitamin D by mouth. It is the genetics of vitamin D metabolism that are providing some answers.

Vitamin D is synthesised by the action of ultraviolet light on 7-dehydrocholesterol (7-DHC). This can take place in the skin and also in marine plankton. The synthesis of vitamin D in this way depends on the amount of 7-DHC available in the skin.
It is interesting that 7-DHC is the precursor not just of vitamin D but also of cholesterol.
It therefore follows that if more cholesterol is produced, there will be less 7-DHC available to be converted into vitamin D. Although the synthesis of vitamin D from 7-DHC is a physico-chemical process of ultraviolet light action, the synthesis of cholesterol from 7-DHC is a biochemical process mediated by the enzyme 7-DHC reductase. This enzyme is genetically determined by the gene identified as DHRC7 (NADSYN). The mutations (polymorphisms) of this gene have been shown to be associated with higher blood levels of vitamin D, as would be predicted.

Vitamin D passes through the liver where it is converted into 25(OH) Vitamin D. This has a low level of biological activity but it is this form of vitamin D that is measured in the blood and it is the best measure of adequacy of vitamin D, of how much vitamin D is either synthesised in the skin or taken in the diet. This conversion process in the liver is under the influence of the enzyme 25- hydroxylase. This is also genetically determined, the gene identified being CYP2R1. Mutations (polymorphisms) of this gene are associated with lower levels of 25(OH)D in the blood due to reduced conversion.

25(OH)D is carried in the blood, bound to vitamin D binding protein (VDB). The production of this is also genetically determined, gene GC. Mutations (polymorphisms) of this gene are associated lower levels of 25(OH)D in the blood.

25(OH)D is converted into the active hormone 1,25(OH)2 Vitamin D. This conversion process is mainly in the kidney but can also occur in other cells. 1,25(OH)2D activates vitamin D receptors (VDR’s) which stimulate a number of intra-cellular processes. They also stimulate vitamin D responsive elements (VDRE) which stimulate further intra-cellular processes and gene control.

It is important that the blood level of 1,25(OH)2D is controlled very closely so as to avoid over- activity. This requires in particular, the enzyme 24-hydroxylase, the activity of which leads to 1,24,25(OH)3 Vitamin D which is an inactive metabolite. 24-hydroxylase is also under genetic control, the gene being CYP24A1. Mutations (polymorphism) of this gene will also have an effect on vitamin D metabolism and effects.

The synthesis of vitamin D by the sun is the first step with a variety of metabolic consequences, which are fundamental to the maintenance of cellular activity and good health.

Further reading:
Common genetic determinants of vitamin D insufficiency: a genome-wide study, Wang TJ et al, Lancet 2010; 376: 180-188

PubMed search for gene OR genetic in title AND "Vitamin d" in title August 2010 got 844 hits of which there were 54 Review, and 223 Open Text

PubMed search for cholesterol AND "Vitamin d" in title, such as
Boosting vitamin D may reduce your heart risk. Research shows that the vitamin helps fight inflammation, lower blood pressure, and may also play a role in controlling cholesterol.

See also at VitaminDWiki
