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（由申请人提供）：维生素 D 调节骨代谢，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。我们的团队利用即将到期的 R01 (DL094486-02) 的资金来研究一种新颖的药物。关于生物可利用维生素 D (BavD) 的假设，即未与维生素 D 结合蛋白 (DBP) 结合的部分，可自由进入细胞并发挥生物效应（Powe 等，2017）。 2013 年，《新英格兰医学杂志》）。我们使用从一生中多样性社区的健康老龄化（HANDLS，美国国立老龄化研究所）研究中获得的大量黑人和白人受试者（n = 2,085）的血液样本。研究发现，尽管美国黑人的 25D 总量低于白人，但考虑到以下因素后，其 BavD 相似：(1) DBP (Gc1F， Gc1S），（2）循环中 DBP 变体的丰度，以及（3）DBP 亲和力结合常数，我们的结论依赖于根据测量的 DBP 浓度和公布的亲和力常数计算出的 BavD 值，因此仅适用于纯合子。尽管存在这一局限性，我们的研究结果还是推进了目前对维生素 D 生物学的理解，可能解释了黑人与白人中维生素 D 和骨密度之间的矛盾关系，以及种族对维生素 D 状态测量的影响。关于维生素D 缺乏症已被定义，并且已被独立描述为对维生素 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直接测量 BavD 的新方法，并加强我们的结论。我们研究的主要局限性，即依赖计算得出的 BavD，因此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。根据现有的测量循环总量的方法25-羟基维生素 D (25D) 与当前标准临床测试的总 25D 水平不同，我们的新方法考虑了 25D 的生物利用度分数，并且与种族或基因型无关，我们计划直接测量以下方面的 BavD。 ) 种族多样化的 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) 绝经过渡期的女性 (SWAN)队列），以评估 BavD 是否比总 25D 更好地反映骨骼健康；（3）具有多种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。我们的团队通过创建“人性化”动物模型来证明导致 DBP 变异的遗传多态性会根据饮食中维生素 D 的含量产生总 25D 和 BavD 的表型（Gc1F、Gc1S）差异。 （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实现本拨款续签申请中提出的具体目标。