Assessing Vitamin D Status: Time for a Rethink?

Abstract

Vitamin D status is universally assessed by measuring circulating total 25-hydroxyvitamin D [25(OH)D]3, the sum of 25(OH)D3 and 25(OH)D2. However, despite the widespread acceptance of this biomarker of vitamin D status, studies have suggested that measurement of 25(OH)D alone may not be sufficient to understand the relationship between vitamin D exposure and certain health outcomes. As a result, attention has turned to other aspects of vitamin D biology. Approximately 90%–95% of 25(OH)D is tightly bound to a specific α globulin, vitamin D binding protein (VDBP), which is structurally related to serum albumin. Of the remaining 25(OH)D, about 1% is unbound and the rest loosely bound to serum albumin. A current hypothesis is that the free and albumin-bound moieties are responsible for delivering 25(OH)D to the cell, with the VDBP-bound 25(OH)D acting as a reservoir of the metabolite. In humans, common genetic polymorphisms produce 3 major circulating variants of the VDBP (Gc1F, Gc2, and Gc1S), which differ in their affinity for 25(OH)D. The prevalence of these polymorphs has been shown to vary across different ethnicities and populations, with the Gc1F variant generally more common among individuals of African ancestry. In a recent study reported in the New England Journal of Medicine (1), Powe et al. investigated the prevalence of the different VDBP phenotypes (Gc1F, Gc2, and Gc1S) in a cohort of black and white Americans and examined the relationship with 25(OH)D concentrations as well as other parameters. Unlike previous investigations, this study included measurements of the concentration of serum VDBP. In this work, black Americans were found to have a preponderance of the high-affinity Gc1F phenotype, with homozygotes having about half the concentration of total VDBP found in whites, in whom the Gc1S variant predominated. The mean concentration of total 25(OH)D was also lower in blacks …