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Title: Role of Assay Type in Determining Free 25-Hydroxyvitamin D Levels in Diverse Populations

Serum 25-hydroxyvitamin D (25OHD) is the most frequently used marker of vitamin D status. Low 25OHD is associated with bone loss, fractures {Cauley, 2010 #1516;Ensrud, 2009 #1517}, and other adverse health outcomes {Theodoratou, 2014 #1518}. Most extra renal tissues only have access to free 25OHD, and free 25OHD concentration is thus a plausible biomarker of 25OHD availability and function {Johnsen, 2014 #1443;Chun, 2014 #1343}. Stronger associations with free or bioavailable 25OHD than with total 25OHD were reported for serum calcium, parathyroid hormone (PTH) {Bhan, 2012 #1124} and bone mineral density (BMD) {Powe, 2011 #1129}. These findings have led to the suggestion that free or bioavailable 25OHD may provide a more clinically relevant measure of tissue 25OHD availability and vitamin D status {Powe, 2013 #1369; Holick NEJM 2013 editorial}. The US Preventive Services Task Force (LeFevre 2015) recently pointed to the gap in research regarding bioavailable and free 25OHD and noted the possibility that these may be better markers of tissue 25OHD availability. Free 25OHD is conventionally calculated from the concentrations of total 25OHD, vitamin D binding protein (DBP) and albumin, with or without a factor accounting for DBP genotype-specific binding affinities {Bouillon, 1981 #1207;Chun, 2012 #1143; Powe, 2011 #1129;Johnsen, 2014more » #1443}. DBP—or Group specific component (GC) {Hirschfeld, 1959 #1468}—polymorphisms (rs4588 and rs7041) give rise to three major polymorphic isoforms of DBP, GC-1F, GC-1S and GC-2, the frequencies of which differ globally, with GC-1F alleles more common in populations of African descent {Kambou, 1986 #1122}. Although DBP is a primary component of free and bioavailable 25OHD calculations, substantial variation in DBP between assays has been noted (Powe suggest to cite here previous publications as in previous version of this Ms). Using DBP measured by a monoclonal antibody Powe et al. {Powe, 2013 #1369} concluded that calculated free 25OHD in African-Americans was equal or higher than in US whites, questioning the implications of low total 25OHD concentrations in African Americans (Holick 2013). This idea gained widespread attention in medical and lay press {LeFevre, 2015 #1598; Bhan, 2014 #1485; Durazo-Arvizu, 2014 #1519}, and many others) and may have important implications for nutrional supplementation policy. To better understand the importance of free 25OHD estimates, and its racial differences, we conducted studies in cohorts based in the US, UK and The Gambia that included participants of African and European ancestry known to differ in GC genotype distribution. We characterized the molecular forms of circulating DBP through comparison of several DBP assays and DBP peptide proteomic analysis, to obtain both calculated and directly measured free 25OHD by geographical region, race and GC genotype.« less
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Publication Date:
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Report Number(s):
Journal ID: ISSN 0028-4793; 48135; 453040220
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Resource Type:
Journal Article
Resource Relation:
Journal Name: New England Journal of Medicine; Journal Volume: 374; Journal Issue: 17
Research Org:
Pacific Northwest National Laboratory (PNNL), Richland, WA (US), Environmental Molecular Sciences Laboratory (EMSL)
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Country of Publication:
United States
Environmental Molecular Sciences Laboratory