Redefining Vitamin D Deficiency: The Role of Bioavailable Vitamin D

 描述（由申请方提供）：维生素D调节骨代谢，可能对其他生理系统产生多效性作用，对健康结果具有潜在的重要影响。来自我们即将到期的R 01（DL 094486 -02）的资金使我们的团队能够研究关于生物可利用维生素D（BavD）的新假设，BavD是一种不与维生素D结合蛋白（DBP）结合的组分，可以自由进入细胞并发挥生物学效应。 2013，新英格兰医学杂志）。使用从一个大型队列的黑人和白色受试者（n= 2，085）中获得的血液样本，这些受试者来自整个生命周期中多样性社区的健康老龄化（HANDLS，美国国立老龄研究所）的研究，我们发现，美国黑人，尽管有低于白人的总25 D，有类似的BavD时，考虑到：（1）DBP的遗传变异（Gc 1F，Gc 1 S），（2）循环中DBP变体的丰度，和（3）DBP亲和结合常数。我们的结论依赖于基于测量的DBP浓度和公布的亲和力常数计算的BavD值，因此仅适用于纯合子个体。尽管存在这种局限性，但我们的研究结果推进了目前对维生素D生物学的理解，可能解释了黑人与白人维生素D和骨密度之间的矛盾关系以及种族对维生素D状态测量的影响。我们的研究结果还提出了关于如何定义维生素D缺乏的重要问题，并被独立地描述为对维生素D水平的解释具有深远的影响。资金的扩展将使我们能够利用我们开发的一种新的检测方法来直接测量BavD，并加强我们的结论。我们将消除我们研究的一个关键限制，即，依赖于计算的BavD。在这样做的过程中，我们有可能直接影响医学研究所（IOM）和其他卫生政策制定者提出的维生素D摄入量建议。此外，我们将改进现有的方法来测量循环总25-羟基维生素D（25 D）。与目前标准临床试验的总25 D水平不同，我们的新方法考虑了25 D的生物可利用部分，并且与种族或基因型无关。我们计划在以下人群中直接测量BavD：（1）不同种族的HANDLS队列，以确认BavD是否是所有种族群体中确定真实维生素D状态的通用标记物;（2）绝经过渡期妇女（SWAN队列），以评估BavD是否比总25 D更好地反映骨健康;（3）具有广泛甲状旁腺激素水平的慢性肾病患者，以评估定义BavD正常与异常截止水平的阈值。我们计划通过创建“人源化”动物模型来补充这些临床研究，以证明导致DBP变体表型（Gc 1F，Gc 1 S）的遗传多态性会根据饮食中维生素D的含量产生总25 D和BavD的差异。我们的团队（临床研究人员/流行病学家，临床化学家和基础科学家）具有互补的技能，并且具有独特的资格来执行此资助更新申请中提出的具体目标。

 DESCRIPTION (provided by applicant): Vitamin D regulates bone metabolism and may exert pleiotropic effects on other physiological systems with potentially important implications for health outcomes. Funding from our soon-to-expire R01 (DL094486-02) enabled our team to investigate a novel hypothesis about bioavailable vitamin D (BavD), the fraction not bound to vitamin D binding protein (DBP) that is free to enter cells and exert biologic effects (Powe et al. 2013, New England Journal of Medicine). Using blood samples obtained from a large cohort of black and white subjects (n=2,085) from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS, National Institutes of Aging) study, we found that black Americans, despite having lower total 25D than whites, have similar BavD when taking into account: (1) genetic variations in DBP (Gc1F, Gc1S), (2) the abundance of DBP variants in the circulation, and (3) DBP-affinity binding constants. Our conclusions relied on calculated BavD values based on measured DBP concentrations and published affinity constants and were therefore applicable only to homozygous individuals. Despite this limitation, our findings advanced the current understanding of vitamin D biology, possibly explaining the paradoxical relationship between vitamin D and bone density in blacks vs whites and the impact of race on measures of vitamin D status. Our findings also raise important questions about how vitamin D deficiency is defined, and have been independently described as having profound implications for interpretation of vitamin D levels. An extension of funding will allow us to utilize a novel assay that we developed to directly measure BavD, and strengthen our conclusions. We will eliminate a key limitation of our study, i.e., reliance on calculated BavD. In doing so, we have the potentia to directly impact recommendations for vitamin D intake set forth by the Institute of Medicine (IOM) and other health policy- makers. Moreover, we will improve upon existing methods for measuring circulating total 25-hydroxyvitamin D (25D). Unlike total 25D levels which are the current standard clinical test, our new approach takes the bioavailable fraction of 25D into account, and is independent of race or genotype. We plan to directly measure BavD in: (1) the racially-diverse HANDLS cohort to confirm whether BavD is the universal marker of choice in all racial groups to determine true vitamin D status; (2) women in the menopausal transition (SWAN cohort), to evaluate whether BavD reflects bone health better than total 25D; (3) chronic kidney disease patients with a wide range of parathyroid hormone levels to evaluate thresholds that define normal vs abnormal cutoff levels for BavD. We plan to complement these clinical studies by creating 'humanized' animal models to prove that genetic polymorphisms resulting in DBP variant phenotypes (Gc1F, Gc1S) produce differences in total 25D and BavD depending on the vitamin D content of the diet. Our team (clinical researchers/epidemiologist, clinical chemist and basic scientist) have complementary skills and are uniquely qualified to carry out the specific aims proposed in this grant renewal application.