Bioavailable Vitamin D Redefines Vitamin D Deficiency

描述（由申请人提供）：维生素D缺乏与骨骼疾病和许多其他主要非骨骼疾病有关，包括心血管疾病、感染、癌症和糖尿病。尽管补充维生素D可能会降低风险，但在不同种族人群中建立临床相关维生素D缺乏症的定义和临界值缺乏共识。作为一项公共卫生重点，确定哪些人需要接受治疗以最佳地影响疾病结局至关重要。黑人的25-羟基维生素D （25[OH] D）水平一直较低，但矛盾的是，他们的骨密度（BMD）高于白人，患骨质疏松症的风险较低。黑人应该服用维生素D来预防骨质疏松吗？我们建议在“游离激素假说”的背景下研究一个新的概念，即维生素D结合蛋白（VDBP）是这一悖论的生理机制的基础。我们最近报道了健康年轻人的VDBP水平：(1)与总25(OH)D水平直接相关；(2)与游离和生物利用度-25(OH)D呈负相关；而且，重要的是，(3)因种族而异。我们的研究小组在ESRD患者和孕妇中收集的初步数据与这些观察结果一致。其他研究表明，VDBP基因的多态性表现出明显的种族差异，这表明VDBP调节维生素D的活性。因此，可能并非所有黑人都有严重的游离性和生物可利用性维生素D缺乏症。我们计划通过比较大量（n~2,200）黑人和白人受试者的储存血液样本来确定循环VDBP对生物可利用性25(OH) D的影响，这些受试者参加了HANDLS(在整个生命周期内多样性社区的健康老龄化（可在http://handls.nih.gov上获得），以检验以下假设：黑人的VDBP和总25(OH) D水平较低，但游离和生物可利用的25(OH) D水平与白人相似。2. 游离和生物可利用25(OH)D水平与黑人和白人的骨密度独立相关，与甲状旁腺激素水平呈负相关和线性相关，这些相关性比总25(OH)D与骨密度之间的相关性更强。我们的具体目标是：(1)测定VDBP、总25(OH)D和生物可利用性25(OH)D和甲状旁腺激素水平；(2)测试骨密度、生物可利用25(OH)D和甲状旁腺激素与总25(OH)D之间的关系。

DESCRIPTION (provided by applicant): Vitamin D deficiency has been associated with bone disease and a host of other major non-skeletal diseases including cardiovascular, infection, cancer and diabetes. Although supplementation may reduce risks, the definitions and cutoffs that establish clinically relevant vitamin D deficiency across racially diverse populations lack consensus. As a public health priority, it is critical to determine who needs to be treated to optimally affect disease outcomes. Blacks consistently have low 25-hydroxy vitamin D (25[OH] D) levels but paradoxically have higher bone mineral density (BMD) and lower osteoporosis risk than whites. Should blacks be treated with vitamin D to prevent osteoporosis? We propose to investigate a novel concept that vitamin D binding protein (VDBP), in the context of the "free hormone hypothesis," underlies the physiological mechanisms of this paradox. We recently reported in healthy young adults that VDBP levels: (1) directly correlate with total 25(OH)D levels; (2) inversely correlate with free- and bioavailable-25(OH)D; and, importantly, (3) vary with race. Preliminary data collected by our research team in patients with ESRD and in pregnant women are consistent with these observations. Others have shown that polymorphisms of the VDBP gene exhibit marked racial differences, suggesting that VDBP modulates vitamin D activity. It is therefore likely that all blacks do not have profound free and bioavailable vitamin D deficiency. We plan to determine the influence of circulating VDBP on bioavailable 25(OH) D by comparing stored blood samples from a large (n~2,200) population of black and white subjects enrolled in HANDLS (Healthy Aging in Neighborhoods of Diversity across the Life Span (available at http://handls.nih.gov) to test the following hypotheses: 1. Blacks have lower levels of VDBP and total 25(OH) D, but similar levels of free and bioavailable 25(OH) D as whites. 2. Free and bioavailable 25(OH)D levels are independently associated with BMD in blacks and whites, inversely and linearly associated with PTH levels, and these associations are stronger than those between total 25(OH)D and BMD. Our specific aims are to: (1) determine VDBP, total and bioavailable 25(OH)D, and PTH levels; and (2) test for associations between BMD, bioavailable 25(OH)D, and PTH compared to total 25(OH)D.