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）稳定了维生素D代谢物的循环浓度和调节 它们输送到组织。许多观察性研究已将DBP的常见遗传变异与风险联系在一起 疾病。其他研究发现这些相同的遗传变异改变了血清总的关系 25-羟基维生素D（25OHD）浓度和疾病结果。有趣的是，这些DBP的变体是 与祖先相关，可能是种族异质性的一部分，总计25OHD-DISESE 协会。很少有研究研究DBP的这种变异如何影响维生素D代谢和 活动。该项目的目的是确定DBP常见遗传变异的机制 影响维生素D代谢。合理的机制或中介因子是25OHD的无血清分数 （免费25OHD百分比）。药代动力学原理预测血清DBP浓度和25OHD-DBP 结合亲和力将确定无25OHD百分比，这将影响组织的可用性和清除率 25ohd。这项研究旨在证实这些预测。第一个研究目的是量化关联 自由25OHD和25OHD代谢清除率之间。我们将在一个巨大的稳定中追求这个目标 同位素示踪25OHD清除的研究，其中包括黑色或白色种族的成年人。对于这个项目，血清 游离25OHD浓度将在基线样品中直接测量，并具有新型的液相色谱 - 串联质谱法。我希望免费百分比25OHD与25OHD呈正相关 代谢清除率，并调解清除与种族和DBP基因型的关联。第二个目标是 量化DBP基因型与自由百分比25OHD和血清25OHD和PTH的关联 对维生素D补充的反应。我们将在维生素的随机对照试验中追求这一目标 D补充嵌套在动脉粥样硬化的多种族研究中 美国成年人。在基线和随访时将测量自由25OHD的血清浓度。我期待 自由25OHD的百分比与DBP基因型不同，我假设DBP基因型会影响25OHD 清除率，因此修饰了血清总计25OHD对补充的反应，但不会修改 免费25OHD或PTH响应。总而言之，该项目将确定是否以及在何种程度上 DBP的遗传变异与25OHD百分比，25OHD清除以及25OHD和PTH有关 对维生素D补充的反应。预期的结果包括一部分的机械解释 血清总计25OHD浓度与健康结果之间的关联的异质性。知识 这项工作产生的可能有助于发现维生素D状态的更具普遍的生物标志物。这 项目将为我提供概念培训的指导培训，并将其用于维生素D的研究 生物学，营养生物标志物，代谢和精确营养。是大型临床研究的辅助 还将增强我在营养研究生涯中的协作科学技能和种子未来的指导。