Bioavailable Vitamin D Redefines Vitamin D Deficiency

描述(申请人提供)：维生素D缺乏与骨骼疾病和许多其他主要的非骨骼疾病有关，包括心血管疾病、感染、癌症和糖尿病。尽管补充剂可能会降低风险，但在不同种族人群中确定临床相关维生素D缺乏症的定义和界限缺乏共识。作为公共卫生优先事项，至关重要的是确定谁需要接受治疗才能以最佳方式影响疾病结果。黑人的25-羟基维生素D(25[OH]D)水平一直较低，但矛盾的是，黑人的骨密度(BMD)比白人高，骨质疏松的风险比白人低。黑人应该服用维生素D来预防骨质疏松症吗？我们建议调查一个新的概念，即维生素D结合蛋白(VDBP)，在“自由荷尔蒙假说”的背景下，是这一悖论的生理机制的基础。我们最近在健康的年轻人中报道，VDBP水平：(1)与总的25(OH)D水平直接相关；(2)与游离的和生物可利用的-25(OH)D水平负相关；以及，重要的是，(3)随种族而异。我们的研究团队在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，很可能并不是所有的黑人都有严重的游离和生物可利用的维生素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25(OH)D的影响。HANDLS(可在http://handls.nih.gov)上获得)登记在HANDLS(社区多样性社区的健康老龄化)中，以检验以下假设：1.黑人的VDBP水平较低，25(OH)D总量较低，但游离和生物可利用25(OH)D水平与白人相似。2.在黑人和白人中，游离25(OH)D和生物可利用25(OH)D水平与骨密度独立相关，与甲状旁腺素水平呈负相关和线性相关，且这些相关性强于25(OH)D总量与BMD之间的关系。我们的具体目标是：(1)测定VDBP、总的和生物可利用的25(OH)D和甲状旁腺素水平；以及(2)测试骨密度、生物可利用的25(OH)D和甲状旁腺素之间的关系。

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.