Gene Variants Associated With Increased Risk for Vitamin D Insufficiency

Jacquelyn K. Beals, PhD

June 11, 2010

June 11, 2010 — A new study by the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT), an international consortium studying genetic influence on vitamin D levels, has found 4 gene variants associated with concentrations of 25-hydroxyvitamin D. The loci encode a protein that binds and transports vitamin D, the enzyme that converts a vitamin D precursor into cholesterol, and a liver enzyme that may enable vitamin D hydroxylation. A fourth variant encodes an enzyme involved in vitamin D degradation.

Published online June 10 in The Lancet, the report notes that up to half the adults in developed countries are deficient in vitamin D. Diet and sunlight exposure influence circulating levels of vitamin D, with levels higher in the summer and lower in the winter. However, "only about a quarter of the interindividual variability in 25-hydroxyvitamin D concentration is attributable to season of measurement, geographical latitude, or reported vitamin D intake," say the authors.

Vitamin D plays a critical role in muscular and skeletal health, and its deficiency has apparent links to diabetes, several cancers, and cardiovascular disease. "There is an association of low vitamin D and high cholesterol, although many non-genetic factors could contribute to this," observed lead author Thomas J. Wang, MD, from the Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, in his email to Medscape Medical News.

The study assessed genetic associations with 2 thresholds of vitamin D insufficiency: circulating concentrations of 25-hydroxyvitamin D lower than 75 nmol/L (30 ng/mL) and lower than 50 nmol/L (20 ng/mL). Drawing the test populations from 15 cohorts of European descent in Europe and North America, the genome-wide association study began with gene discovery in 5 groups (n = 16,125) from whom genotype data and 25-hydroxyvitamin D concentrations were obtained.

Single-nucleotide polymorphisms (SNPs) significantly associated with 25-hydroxyvitamin D concentration at the genome-wide association study level (P < 5 × 10−8) were analyzed further in 5 groups designated "replication cohorts" (n = 9367); finally, selected variants were assessed in a "de novo" replication group of 4 cohorts not previously analyzed and 1 of the discovery cohorts (n = 8504). Selected genetic variants (likely candidates for vitamin D association) were also analyzed.

Significant association was found between 25-hydroxyvitamin D levels and SNPs on chromosome 4 (4p12) and chromosome 11 (11q12 and 11p15). These loci are in or near the genes GC, DHCR7/NADSYN1, or CYP2R1; the P values in replication samples for the most strongly associated SNP at each locus were 2.9 × 10−48, 2.4 × 10−16, and 2.1 × 10−14, respectively. Only 1 candidate gene was strong enough to replicate: CYP24A1 (on chromosome 20), for which P = 8.4 × 10−8 in the replication cohorts.

The genetic variants identified in this study have logical associations with vitamin D: GC encodes a vitamin D binding protein, CYP2R1 encodes a microsomal liver enzyme that may be responsible for vitamin D hydroxylation, and DHCR7/NADSYN1 encodes an enzyme that converts a vitamin D precursor into cholesterol, thus decreasing the amount of precursor that becomes vitamin D.

Doubts That Genetic Screening Will Be Implemented

More important, clinically, the study assessed whether the 3 main variants affect risk for vitamin D insufficiency. Individuals scoring in the top quartile (combining the 3 risk variants) had odds ratios [ORs] of 2.47 (95% confidence interval [CI], 2.20 - 2.78; P = 2.3 × 10−48) for vitamin D levels lower than 75 nmol/L; for vitamin D levels below 50 nmol/L, the OR was 1.92 (95% CI, 1.70 - 2.16; P = 1.0 × 10−26.

Excessive vitamin D may cause gastrointestinal, renal, and cardiovascular problems. Medscape Medical News asked Dr. Wang whether genetic screening could indicate which patients can tolerate (benefit from) "excessive" vitamin D supplements. "Any clinical use would be premature," said Dr. Wang, "because studies have not been done yet examining whether these variants alter response to supplementation. But this will be an important area of future investigation," he noted.

An additional perspective was expressed by Roger Bouillon, MD, PhD, from the Clinic and Laboratory of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Belgium, author of a related comment in the same issue of The Lancet.

"In view of the costs of genetic screening in comparison with the actual 25-hydroxyvitamin D measurement and the relatively cheap cost of vitamin D supplements, I think that genetic screening will not be implemented here," said Dr. Bouillon via email to Medscape Medical News.

Broad Effects of Vitamin D Insufficiency

Potential implications of the findings are not limited to musculoskeletal diseases. Studies in recent years have found that children with inflammatory bowel disease often have lower levels of vitamin D than their healthy peers. Low levels of vitamin D also have been associated with dementia, stroke, and cerebrovascular disease, indicating a possible protective role of vitamin D in vascular disease. Low levels of vitamin D and calcium may also increase blood glucose levels, and supplements improve glucose metabolism.

Adequate sunlight exposure and vitamin D have even been implicated in multiple sclerosis risk, suggesting that vitamin D supplements may have a role in prevention of multiple sclerosis. "There are cellular/biochemical/animal data that support a link between vitamin D deficiency and autoimmune diseases," said Dr. Bouillon. "In humans, there is a link between low vitamin D status and higher subsequent risk for [multiple sclerosis], but also for type 1 diabetes or inflammatory bowel disease.

"However, there are no randomized controlled...intervention trials to prove a causal link, and ditto for all the other nonskeletal diseases," said Dr. Bouillon. "The only exception is [that] vitamin D supplements can reduce the risk of falls."

In his editorial, Dr. Bouillon concludes: "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."

Dr. Wang has served on the scientific advisory board of Diasorin. Several of the other authors have served on scientific advisory boards, received honoraria and speakers fees, acted as consultants for, and/or own stock in one or more of the following companies: Abbot Nutrition, Amgen, Astra Zeneca, Genzyme, GlaxoSmithKline, Novartis, Merck, Pfizer, Roche, and Shire. Dr. Bouillon has been a consultant for Eli Lilly, Amgen, and MSD, and has received royalties from Hybrigenix for a vitamin D analogue.

Lancet. Published online June 10, 2010.


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