Redefining Vitamin D Deficiency: The Role of Bioavailable Vitamin D

重新定义维生素 D 缺乏症：生物可利用维生素 D 的作用

• 批准号: 9015435
• 负责人: S. Ananth Karumanchi
• 金额: $ 44.07万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-17 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9015435
• 关键词: 25-hydroxyvitamin D; Accounting; Affinity; African American; Age; Aging; American; Animal Model; Animals; Area; Binding; Binding Proteins; Bioavailable; Biological Assay; Biological Markers; Biology; Blood Circulation; Blood specimen; Bone Density; Cells; Chronic Kidney Failure; Clinical; Clinical Research; Complement; Data; Diet; Disease Outcome; Epidemiologist; Foundations; Funding; Future; Gender; Genes; Genetic Polymorphism; Genetic Variation; Genotype; Grant; Health; Health Care Research; Health Policy; Human; Human Genetics; Individual; Institute of Medicine (U.S.); Institutes; Intake; Investigation; Journals; Kidney; Kidney Diseases; Knock-in Mouse; Liquid substance; Longevity; Measures; Medicine; Menopause; Methods; Mus; Neighborhoods; New England; Outcome; PTH gene; Patients; Phase; Phenotype; Physiological; Policy Maker; Population; Public Health; Publishing; Qualifying; Race; Recommendation; Research; Research Personnel; Risk; Role; Scientist; Secondary Hyperparathyroidism; Societies; Solid; System; Testing; Translational Research; Variant; Vitamin D; Vitamin D Deficiency; Vitamin D-Binding Protein; Woman; Work; base; bone health; bone metabolism; caucasian American; clinical decision-making; clinically relevant; clinically significant; cohort; genetic variant; health care quality; healthy aging; improved; innovation; novel; novel strategies; pleiotropism; racial diversity; repository; research clinical testing; research study; screening; skills

 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.

 描述(申请人提供)：维生素D调节骨骼新陈代谢，并可能对其他生理系统产生多效性影响，对健康结果具有潜在的重要影响。我们即将到期的R01(DL094486-02)的资金使我们的团队能够研究关于生物可用维生素D(BavD)的新假说，BavD是一种不与维生素D结合蛋白(DBP)结合的部分，可以自由进入细胞并发挥生物效应(Power等人)。 2013，《新英格兰医学杂志》)。使用从社区多样性健康老龄化研究(HANDLS，National Institutes of Aging)研究中获得的大量黑人和白人受试者(n=2,085)的血液样本，我们发现，尽管美国黑人的25D总数比白人低，但考虑到：(1)DBP(Gc1F，Gc1S)的遗传变异，(2)循环中DBP变异的丰度，以及(3)DBP亲和力结合常数，美国黑人具有相似的BavD。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。尽管存在这一局限性，我们的发现还是推进了目前对维生素D生物学的理解，可能解释了黑人和白人中维生素D和骨密度之间的矛盾关系，以及种族对维生素D状态衡量标准的影响。我们的发现也提出了关于如何定义维生素D缺乏症的重要问题，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。资金的延长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，即依赖计算的BavD。通过这样做，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，我们将改进现有的循环总25-羟基维生素D(25D)的测定方法。与目前标准的临床试验总25D水平不同，我们的新方法考虑了25D的生物可利用度，并且与种族或基因无关。我们计划在以下方面直接测量BavD：(1)不同种族的HANDLS队列研究，以确定BavD是否是所有种族群体确定真正维生素D状况的通用标记物；(2)绝经过渡期妇女(Swan队列)，评估BavD是否比总25D更能反映骨骼健康；(3)对有广泛甲状旁腺激素水平范围的慢性肾病患者进行BavD检测，以评估BavD正常与异常界值的界限。我们计划通过创建人性化的动物模型来补充这些临床研究，以证明导致DBP变异表型(Gc1F和Gc1S)的基因多态会根据饮食中维生素D含量的不同而导致总25D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)拥有互补的技能，并且唯一有资格实现本次拨款续签申请中提出的具体目标。