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Vitamin D insufficiency 2.5X more likely with three genes – Lancet July 2010

Common genetic determinants of vitamin D insufficiency: a genome-wide association study.

Lancet. 2010 Jul 17;376(9736):180-8. Epub 2010 Jun 10.
Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, Peltonen L, Cooper JD, O'Reilly PF, Houston DK, Glazer NL, Vandenput L, Peacock M, Shi J, Rivadeneira F, McCarthy MI, Anneli P, de Boer IH, Mangino M, Kato B, Smyth DJ, Booth SL, Jacques PF, Burke GL, Goodarzi M, Cheung CL, Wolf M, Rice K, Goltzman D, Hidiroglou N, Ladouceur M, Wareham NJ, Hocking LJ, Hart D, Arden NK, Cooper C, Malik S, Fraser WD, Hartikainen AL, Zhai G, Macdonald HM, Forouhi NG, Loos RJ, Reid DM, Hakim A, Dennison E, Liu Y, Power C, Stevens HE, Jaana L, Vasan RS, Soranzo N, Bojunga J, Psaty BM, Lorentzon M, Foroud T, Harris TB, Hofman A, Jansson JO, Cauley JA, Uitterlinden AG, Gibson Q, Järvelin MR, Karasik D, Siscovick DS, Econs MJ, Kritchevsky SB, Florez JC, Todd JA, Dupuis J, Hyppönen E, Spector TD.
Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. tjwang at partners.org
Comment in:
* Lancet. 2010 Jul 17;376(9736):142.
* Lancet. 2010 Jul 17;376(9736):148-9.
Comment on:
* Lancet. 2010 Jul 17;376(9736):142.

BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.

METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.

FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile.

INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. PMID: 20541252

Following from USDA web site http://www.ars.usda.gov/research/publications/Publications.htm?seq_no_115=253697

Interpretive Summary:

Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D deficiency has been linked to a number of other disorders , including diabetes, cancer, and cardiovascular disease. In humans, vitamin D concentrations are determined by sun exposure and dietary intake, but there is also evidence suggesting that genetic factors may also play a role. We performed a genome-wide association study of vitamin D concentrations among ~30,000 individuals of European descent from 15 different studies. Five studies were designated as discovery studies (studying 16,125 individuals), in which the genetic factors influencing vitamin D concentrations were identified. There were 10 additional studies (studying 17,744 individuals) used to replicate the findings from the discovery studies. Vitamin D insufficiency was defined as vitamin D concentrations below 75 nmol/L. Variants near genes involved in
cholesterol synthesis (DHCR7),
hydroxylation (CYP2R1 and CYP24A1), and
vitamin D transport (GC)
were found to influence vitamin D concentrations.
These variants were significant in the discovery cohorts and confirmed in the replication cohorts. A genotype score was constructed using these three confirmed variants.

Those with the highest genotype scores had a 2.5-fold greater likelihood of vitamin D insufficiency. In conclusion, genetic variation identifies individuals of European descent who have substantially elevated risk of vitamin D deficiency. The results are valuable for human nutrition managements.

Comment on article by Dr David S Grimes MD FRCP Consultant Physician, Royal Blackburn Hospital

His web site http://www.vitamin-d-deficiency.co.uk/
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.

Comment by US National Library of Medicine Aug 30 2010

NLM Director's Comments Transcript: Vitamin D Deficiencies & Genetics 08/30/2010
Greetings from the National Library of Medicine and MedlinePlus.gov
Regards to all our listeners!

I'm Rob Logan, Ph.D. senior staff National Library of Medicine for Donald Lindberg, M.D, the Director of the U.S. National of Medicine.

Here is what's new this week in MedlinePlus.CLICK HERE to HEAR
Genetic differences should be added to the reasons why an estimated one billion adults around the world have vitamin D deficiencies, suggests a study recently published in The Lancet.

The study's authors, who are part of the Sunlight research consortium of scientists and physicians in several nations, note prior to the current study a combination of personal, social, and cultural factors were known to influence vitamin D levels.

In the current study, the authors found genes that influence how cholesterol is used in the human body, the transport of vitamin D, plus other foundational biochemical processes impact the risk of an individual's vitamin D deficiency. The study of more than 30,000 persons suggests genetic influences are sufficient to add to the non-genetic reasons why concentrations of vitamin D vary significantly among adults – and why vitamin D deficiency remains a serious international medical problem. Eventually, this line of research could help identify who is most at risk of vitamin D deficiency and related diseases.

A commentary that accompanies the study in The Lancet notes future researchers need to explain if genetic differences remain similar if a person receives vitamin D naturally (from sunlight or diet) compared to vitamin D supplements or pills. The author of the commentary also suggests future researchers should assess if the same or different genes impact individual vitamin D levels among diverse populations. The author notes vitamin D levels can be different based on skin pigmentation, race, and ethnicity, so a broader population assessment of genetic/vitamin D deficiency patterns needs to occur.

The author notes (and we quote); 'we need additional studies to explain the mechanisms underlying the pandemic vitamin D deficiency and above all, we need a strategy to correct this serious worldwide deficiency' (end of quote).

The Sunlight consortium authors explain vitamin D comes from sun exposure and diet. They add there is a researched association between vitamin D shortages occurring in winter months and in climates where there is reduced sun exposure. We did a podcast on the seasonal-vitamin D link last year.

Similarly, there are vitamin D shortages in parts of the world where men and women routinely wear clothes that cover their body (which prevents sun exposure), as well as in areas where there is reduced access to foods high in vitamin D, or they are unpopular.

MedlinePlus.gov's vitamin D health topic page notes some foods rich in vitamin D include: egg yolks, saltwater fish, and liver. Vitamin D often is added to milk and breakfast cereals and is widely available as a supplement. A check of two U.S. national drug store chains finds over-the-counter vitamin D supplements cost as little as five cents per pill.

MedlinePlus.gov's vitamin D health topic page explains vitamin D helps the body absorb calcium, which bones need to grow. Vitamin D also influences nerves, muscles and the immune system by among other things, helping to maintain a healthy balance of calcium and phosphorous in your blood stream.

Certainly, vitamin D is not a new medical challenge; researchers first linked vitamin D deficiencies to rickets, or soft, weak bones in children, about 90 years ago. While rickets remains an international health challenge, the author of The Lancet commentary notes vitamin D deficiency also is linked to osteoporosis-related bone loss and injuries from falls and fractures among seniors. In addition, the author explains vitamin D deficiencies are associated with the development of cancer and heart disease.

In an editorial that accompanies the new findings and the aforementioned commentary, The Lancet adds one primary challenge to encourage persons to obtain more natural vitamin D is to educate adults and children about safe sun exposure. While sunshine is a natural source of vitamin D, the editorial emphasizes frequent sun exposure also is linked to skin cancer. The Lancet editorial highlights an Australian educational effort that recommends specific outdoor sun exposure times depending on where persons live and the time of year. The Lancet editors imply similar educational programs within regions and cities in other nations could help adults and children better gauge safe sun exposure.

MedlinePlus.gov's vitamin D health topic page provides an array of helpful information about the diagnosis/symptoms of deficiency, as well as specific related issues, such as the National Osteoporosis Foundation's updated recommendations for calcium and vitamin D intake.

A website from Harvard Medical School (available in the 'overviews' section) provides basic information about vitamin D and health.

You can find the latest journal articles plus overviews of vitamin D research, which are available in the 'journal articles' and 'research' sections respectively. You can find vitamin D clinical trials that may be occurring in your area within the 'clinical trials' section. Also, MedlinePlus.gov's vitamin D health topic page contains information tailored for children.

To find MedlinePlus.gov's vitamin D health topic page, type 'vitamin D' in the search box on MedlinePlus.gov's home page. Then, click on 'vitamin D (National Library of Medicine).' MedlinePlus.gov also has health topic pages devoted to rickets, sun exposure, and skin cancer.

For the moment, vitamin D is an old medical challenge where some new, basic science eventually may explain who is at a deficiency risk. Let's hope a better understanding of how vitamin D levels are genetically influenced, coupled with future educational strategies, will help more adults and kids enjoy safe sunshine, improve bone health, and prevent pernicious vitamin D deficits around the world.
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