Genes May Play a Role in Vitamin D Deficiency – June 2010

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

The Lancet, Early Online Publication, 10 June 2010, doi:10.1016/S0140-6736(10)60588-0
Thomas J Wang MD a e f *Corresponding AuthorEmail Address, Feng Zhang PhD g *, J Brent Richards MD h j k l *, Bryan Kestenbaum MD m *, Joyce B van Meurs PhD r u *, Diane Berry MSc v *, Douglas P Kiel MD d f, Elizabeth A Streeten MD w, Prof Claes Ohlsson PhD x, Daniel L Koller PhD z, Prof Leena Peltonen PhD aa ab ac †, Jason D Cooper PhD ad, Paul F O'Reilly PhD ae, Denise K Houston PhD af, Nicole L Glazer PhD n o, Liesbeth Vandenput PhD x, Prof Munro Peacock DSc(Med) z, Julia Shi MSc w, Fernando Rivadeneira PhD r u, Prof Mark I McCarthy FMedSci ah ai ak, Pouta Anneli PhD al, Ian H de Boer MD m, Massimo Mangino PhD g, Bernet Kato PhD g, Deborah J Smyth BSc ad, Prof Sarah L Booth PhD am, Paul F Jacques ScD am, Prof Greg L Burke MD ag, Prof Mark Goodarzi PhD an, Ching-Lung Cheung PhD d ao, Myles Wolf MD ap, Kenneth Rice PhD n o, Prof David Goltzman MD i j, Nick Hidiroglou PhD aq, Martin Ladouceur PhD h j k l, Prof Nicholas J Wareham PhD ar, Lynne J Hocking PhD as, Deborah Hart PhD g, Prof Nigel K Arden MD aj at, Prof Cyrus Cooper FMedSci aj at, Suneil Malik PhD au, Prof William D Fraser MD av, Prof Anna-Liisa Hartikainen PhD aw, Guangju Zhai PhD g, Helen M Macdonald PhD as, Nita G Forouhi FFPH ar, Ruth JF Loos PhD ar, Prof David M Reid MD as, Alan Hakim MA az, Elaine Dennison PhD at, Yongmei Liu PhD af, Prof Chris Power PhD v, Helen E Stevens HNC ad, Laitinen Jaana PhD ax ba, Prof Ramachandran S Vasan DM f bb, Nicole Soranzo PhD g aa, Jörg Bojunga MD bd, Prof Bruce M Psaty PhD n p q, Mattias Lorentzon PhD x, Prof Tatiana Foroud PhD z, Tamara B Harris MD be, Prof Albert Hofman MD s u, Prof John-Olov Jansson PhD y, Jane A Cauley PhD bf, Prof Andre G Uitterlinden PhD r s t u, Quince Gibson MBA r, Prof Marjo-Riitta Järvelin PhD ae al ax ay, David Karasik PhD d, Prof David S Siscovick MPH n o p, Prof Michael J Econs MD z, Prof Stephen B Kritchevsky PhD af, Jose C Florez PhD b c e bg, Prof John A Todd PhD ad *, Prof Josee Dupuis PhD f bc *, Elina Hyppönen PhD v
*Corresponding AuthorEmail Address, Prof Timothy D Spector MD g *Corresponding AuthorEmail Address

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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=1·9×10?109 for rs2282679, in GC); 11q12 (p=2·1×10?27 for rs12785878, near DHCR7); and 11p15 (p=3·3×10?20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6·0×10?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=2·3×10?48) or lower than 50 nmol/L (1·92, 1·70—2·16, p=1·0×10?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.

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Study Shows 4 Gene Variants May Indicate Risk of Having Low Levels of Vitamin D

By Katrina Woznicki
WebMD Health News, Reviewed by Laura J. Martin, MD
http://www.webmd.com/news/20100609/genes-may-play-arole-in-vitamin-d-deficiency

June 9, 2010 - - Having too little vitamin D may not be due solely to diet or lack of sunlight, but may be due to your genes.

An international consortium of researchers and doctors has identified four gene variants that may play a role in vitamin D deficiency, a condition which may affect up to half of all healthy adults in the developed world. It can contribute to poor musculoskeletal health as well as potentially increase the risk of diabetes, cardiovascular disease, and certain types of common cancers.

Knowing who carries the gene variants could help doctors identify who is at risk for vitamin D deficiency and could potentially help reduce the risk of low vitamin D before the problem advances.

Researchers in the SUNLIGHT Consortium (Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits) analyzed data from 15 epidemiologic groups that included nearly 34,000 whites of European ancestry. The team looked at vitamin D concentration levels in the blood as well as genetics. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L (nanomoles per liter) or 50 nmol/L.

Three common gene variants - - including those involved with cholesterol, vitamin D metabolism, and transporting vitamin D throughout the body - were associated with vitamin D deficiencies. The researchers found that the more of these variants an individual had, the greater the risk of having low vitamin D levels.

In fact, individuals who had inherited several of the gene variants and who fell in the highest quartile in the group had a two-and-a-half times increased risk of having a blood vitamin D concentration that was lower than 75 nmol/L when compared with those in the lowest quartile, who had fewer of these gene variants and were at a lower risk.
The findings will be published in The Lancet and were released online early.
Rethinking Treatment Strategy
The researchers say the results may make doctors rethink treatment strategies for improving patients' vitamin D deficiencies. However, they note that they only studied white populations, so it is unclear if these gene variants would be identified in other racial/ethnic groups.

"It's possible that these results could explain why some people respond well to vitamin D supplements and others don't, but that needs to be studied further since we didn't specifically examine response to supplementation," said Thomas Wang, MD, a consortium member and cardiologist at Massachusetts General Hospital in Boston, who co-authored the report. "We also need to investigate how genetic background can modify response to sunlight, whether these associations are seen in other populations, and if these gene variants have an impact in the chronic diseases that appear to be associated with vitamin D deficiency."

In an accompanying editorial published in The Lancet, Roger Bouillon, MD, from the Katholieke Universiteit in Leuven, Belgium, writes: "Today's results only partly explain the wide variability of vitamin D status, and whether these genetically based variations modify the health outcomes in vitamin D deficiency is not known. Therefore the battle against vitamin D deficiency will probably not be modified by these new findings. We need additional studies to explain the mechanisms underlying the pandemic of vitamin D deficiency and, above all, we need a strategy to correct this serious worldwide deficiency.”

Vitamin D is essential for calcium absorption and bone health; it helps regulate immune function, among other roles. Vitamin D is naturally produced in the skin when you are outside exposed to ultraviolet light from the sun.

Foods that naturally contain vitamin D include fish (particularly salmon and tuna) shrimp, and eggs. Many foods are now fortified with vitamin D, including milk and other dairy products, to boost overall vitamin D intake. Taking a dietary supplement containing vitamin D is also a common way to maintain sufficient vitamin D levels.

See also VitaminDWiki

• Vitamin D dose size needed – VitD testing tells only a portion of the story – Jan 2016
• Genes and Vitamin D – literature review – Dec 2015
• Some of Us May Need More Vitamin D Than Others - Sept 2015
• Genetics category listing contains the following

344 articles in the Genetics category

see also

• Vitamin D Receptor has 530 items
• Vitamin D Binding Protein = GC has 178 items
• CYP27B1 has 63 items
• CYP24A1 in title of 39+ items
• CYP2R1 25+ items
• Calcidiol has 48 items
• Calcitriol has 62 items
• Topical Vitamin D
• Nanoemulsion Vitamin D may be a substantially better form
• 1289 genes changed with higher doses of Vitamin D - RCT Dec 2019
• CYP3A4 (7 as of Dec 2022)
• Getting Vitamin D into your body
• 

Vitamin D blood test misses a lot

• Vitamin D from coming from tissues (vs blood) was speculated to be 50% in 2014, and by 2017 was speculated to be 90%
• Note: Good blood test results (> 40 ng) does not mean that a good amount of Vitamin D actually gets to cells
• A Vitamin D test in cells rather than blood was feasible (2017 personal communication)   Commercially available 2019
  • However, test results would vary in each tissue due to multiple genes
• Good clues that Vitamin D is being restricted from getting to the cells
  1) A vitamin D-related health problem runs in the family
      especially if it is one of 51+ diseases related to Vitamin D Receptor
  2) Slightly increasing Vitamin D shows benefits (even if conventional Vitamin D test shows an increase)
  3) DNA and VDR tests - 100 to 200 dollars $100 to $250
  4) PTH bottoms out ( shows that parathyroid cells are getting Vitamin d)
     Genes are good, have enough Magnesium, etc.
  5) Back Pain
     probably want at least 2 clues before taking adding vitamin D, Omega-3, Magnesium, Resveratrol, etc
  • The founder of VitaminDWiki took action with clues #3&5

The TOP Gene articles are here: