Genetic and environmental determinants of vitamin D status.

Vitamin D, discovered nearly a century ago, still receives intensive attention worldwide. In The Lancet today, Thomas Wang and colleagues, through a monumental eff ort by a large consortium of experts (the SUNLIGHT consortium), provide new data that help to explain the large variability of vitamin D status, as revealed by serum concentrations of 25-hydroxyvitamin D. Vitamin D defi ciency, even when defi ned con servatively as a concentration of 25-hydroxyvitamin D lower than 50 nmol/L, is common and probably aff ects more than one billion people worldwide. This defi ciency causes rickets, which is still highly prevalent around the world, and accelerates age-related bone loss and morbidity from falls and fractures. Moreover, vitamin D insuffi ciency is associated with nearly all major diseases of the developed world, such as cancer, immune diseases, cardiovascular risks, and all factors of the metabolic syndrome. Vitamin D status is thought to depend mainly on endogenous conversion of 7-dehydrocholesterol (7-DHC) into (pre)vitamin D3 during exposure to ultraviolet B from sunlight and to only partly depend on nutritional vitamin D intake, because most common foods, apart from fatty fi sh, have very low vitamin D content. Moreover, most experts believe that the production of 25-hydroxyvitamin D is poorly regulated and largely depends on access to its substrate, vitamin D3. Serum 25-hydroxyvitamin D ceases to increase linearly with vitamin D intake only at much higher concentrations than the usual intake. Overall vitamin D status around the world lies at a mean concentration of about 50 nmol/L with little variation between countries (mean concentrations in diff erent countries grossly fl uctuate between 30 and 75 nmol/L) and much greater variation within countries (from lower than 20 to 200 nmol/L). Data from today’s genome-wide association study, taken from about 30 000 white people drawn from initially fi ve, and later 15, major epidemiological cohorts, show that at least three, and probably four, genes contribute to the variability of serum concentrations of 25-hydrox yvitamin D. Indeed, the relative diff erences in mean 25-hydroxyvitamin D con centration between minor and major homozygotes for the strongest genetic variants were close to those seen with usual vitamin D supplementation, and nearly as large as those seen with seasonal variation between winter and summer. However, this combined gene eff ect is much lower than the heritability predicted on the basis of twin studies. The genes involved encode three key enzymes: 7-DHC reductase (responsible for the availability of 7-DHC in the skin), the liver 25-hydroxylase CYP2R1 (involved in the conversion of vitamin D into 25-hydroxyvitamin D), and CYP24A1 (a key degradation enzyme). Additionally, polymorphisms in GC, the gene encoding vitamin D binding-protein, had the greatest eff ect on serum 25-hydroxyvitamin D concentration. Participants in the top quartile of genotype scores had about twofold elevated odds of vitamin D insuffi ciency. These results thus help to explain the variation in serum 25-hydroxyvitamin D status and show that, indeed, some gene polymorphisms might protect against, or accelerate, vitamin D defi ciency. Some of today’s results were unexpected. None of the identifi ed genes proved to be linked with skin pigmentation, even though skin pigmentation is known to be a major factor in vitamin D status. Moreover, no genes that are linked with any of the major diseases associated with vitamin D defi ciency were picked up. This fi nding suggests that vitamin D status, rather than gene polymorphisms, infl uences these health problems. Today’s study also generates new questions. Do these genes also modify the 25-hydroxy vita min D re sponse to vitamin D supplement ation, and should we take this into account when pre scrib ing vita min D, as suggested?