Common Genetic Variation of Vitamin D Binding Protein and Vitamin D Kinetics

维生素 D 结合蛋白和维生素 D 动力学的常见遗传变异

• 批准号: 10312257
• 负责人: CORA M BEST
• 金额: $ 6.27万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-03 至 2022-08-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312257
• 关键词: 25-hydroxyvitamin D; Adult; Affect; Affinity; African; African American; Binding Proteins; Biological Markers; Biology; Black race; Blood; Caucasians; Clinical Research; Clinical Trials; Data; Disease; Disease Outcome; Drug Kinetics; Ethnic Origin; European; Future; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Gold; Guidelines; Health; Heterogeneity; Individual; Kinetics; Knowledge; Link; Liquid Chromatography; Measures; Mediating; Mentors; Metabolic; Metabolism; Methodology; Methods; Multi-Ethnic Study of Atherosclerosis; Nutritional; Observational Study; Outcome; PTH gene; Participant; Plasma; Population; Race; Randomized Controlled Trials; Research; Risk; Sampling; Science; Scientist; Seeds; Serum; Supplementation; Testing; Tissues; Tracer; Training; Variant; Vitamin D; Vitamin D Deficiency; Vitamin D Nutrition; Vitamin D supplementation; Vitamin D-Binding Protein; Work; adverse outcome; biomarker discovery; career; caucasian American; cohort; disorder risk; enzyme activity; ethnic diversity; follow-up; genetic variant; improved; inter-individual variation; interest; novel; nutrition; precision nutrition; predictive marker; racial and ethnic; response; sample archive; skeletal; skills; stable isotope; tandem mass spectrometry; treatment response

PROJECT SUMMARY/ABSTRACT Vitamin D binding protein (DBP) stabilizes circulating concentrations of vitamin D metabolites and modulates their delivery to tissues. Many observational studies have linked common genetic variants of DBP to risk for disease. Other studies have found these same genetic variants modify the relationship between serum total 25-hydroxyvitamin D (25OHD) concentration and disease outcomes. Of interest, these variants of DBP are associated with ancestry and may underlie a portion of the racial heterogeneity in total 25OHD-disease associations. Few studies have investigated how this variation of DBP affects vitamin D metabolism and activity. The goal of this project is to identify mechanisms through which common genetic variants of DBP affect vitamin D metabolism. A plausible mechanism or mediating factor is the serum free fraction of 25OHD (percent free 25OHD). Pharmacokinetic principles predict that serum DBP concentration and 25OHD-DBP binding affinity will determine the percent free 25OHD, which will influence tissue availability and clearance of 25OHD. This study seeks to substantiate these predictions. The first research aim is to quantify the association between percent free 25OHD and 25OHD metabolic clearance. We will pursue this aim within a large stable isotope tracer study of 25OHD clearance that included adults of Black or White race. For this project, serum free 25OHD concentration will be directly measured in baseline samples with a novel liquid chromatography- tandem mass spectrometry method. I expect the percent free 25OHD to be positively related to 25OHD metabolic clearance and to mediate associations of clearance with race and DBP genotype. The second aim is to quantify associations of DBP genotypes with the percent free 25OHD and the serum 25OHD and PTH responses to vitamin D supplementation. We will pursue this aim within a randomized controlled trial of vitamin D supplementation nested in the Multi-Ethnic Study of Atherosclerosis (MESA), an ethnically diverse cohort of U.S. adults. Serum concentrations of free 25OHD will be measured at baseline and follow-up. I expect the percent free 25OHD to differ by DBP genotype, and I hypothesize that DBP genotype influences 25OHD clearance, therefore modifies the serum total 25OHD response to supplementation but does not modify the free 25OHD or PTH response. In summary, this project will determine whether and to what extent common genetic variation of DBP is associated with percent free 25OHD, 25OHD clearance, and the 25OHD and PTH responses to vitamin D supplementation. Anticipated results include a mechanistic explanation for a portion of the heterogeneity in associations between serum total 25OHD concentration and health outcomes. Knowledge generated by this work may contribute to discovery of more generalizable biomarkers of vitamin D status. This project will provide me with mentored training in concepts and approaches germane to the study of vitamin D biology, nutritional biomarkers, metabolism, and precision nutrition. Being ancillary to large clinical studies, it will also enhance my collaborative science skills and seed future directions for my research career in nutrition.

项目摘要/摘要 维生素D结合蛋白(DBP)稳定循环中维生素D代谢物的浓度并调节 它们被送到纸巾上。许多观察性研究已经将常见的DBP基因变异与患DBP的风险联系起来 疾病。其他研究发现，这些相同的基因变异改变了血清总含量之间的关系 25-羟基维生素D(25OHD)浓度和疾病结局。有趣的是，DBP的这些变体是 与祖先有关，并可能是全部25OHD-疾病中种族异质性的一部分基础 联想。很少有研究调查DBP的这种变异如何影响维生素D代谢和 活动。该项目的目标是确定常见的DBP遗传变异的机制 影响维生素D代谢。一个合理的机制或中介因素是25OHD的血清游离部分 (25OHD百分比免费)。药代动力学原理预测DBP血药浓度和25OHD-DBP 结合亲和力将决定游离25OHD的百分比，这将影响组织的利用度和清除量 25OHD。这项研究试图证实这些预测。第一个研究目标是量化这种联系。 在25OHD和25OHD代谢清除率之间。我们将在一个大马厩内实现这一目标 包括黑人或白人成年人在内的25OHD清除的同位素示踪研究。在这个项目中，血清 游离态25OHD浓度将用一种新的液相色谱直接在基线样品中测量-- 串联质谱法。我预计25OHD的免费百分比与25OHD呈正相关 代谢清除量和调节清除量与种族和DBP基因的关联。第二个目标是 DBP基因分型与游离25OHD百分比、血清25OHD和PTH的相关性 对补充维生素D的反应。我们将在维生素的随机对照试验中追求这一目标 D补充剂嵌套在动脉粥样硬化的多种族研究(MESA)中，这是一个种族多样化的 美国成年人。血清游离25OHD浓度将在基线和随访时进行测定。我期待着 25OHD的百分比因DBP基因而异，我假设DBP基因影响25OHD 因此，Clearance改变了血清对补充的总25OHD反应，但不改变 免费的25OHD或PTH响应。总之，这个项目将决定是否以及在多大程度上是共同的 DBP的遗传变异与25OHD、25OHD清除率、25OHD和PTH相关 对补充维生素D的反应。预期的结果包括对部分 血清总25OHD浓度与健康结局相关性的异质性。知识 这项工作产生的可能有助于发现更具普遍性的维生素D状态的生物标志物。这 该项目将为我提供与维生素D研究相关的概念和方法方面的指导培训 生物学、营养生物标志物、新陈代谢和精确营养。作为大型临床研究的辅助工具，它 还将增强我的协作科学技能，并为我在营养方面的研究生涯指明未来的方向。