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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要维生素 D 结合蛋白 (DBP) 可稳定维生素 D 代谢物的循环浓度并进行调节它们输送到组织。许多观察性研究已将 DBP 的常见遗传变异与罹患癌症的风险联系起来。疾病。其他研究发现，这些相同的遗传变异改变了血清总量之间的关系。 25-羟基维生素 D (25OHD) 浓度和疾病结果。有趣的是，DBP 的这些变体是与血统相关，可能是 25OHD 疾病中种族异质性的一部分协会。很少有研究调查 DBP 的这种变化如何影响维生素 D 代谢和活动。该项目的目标是确定 DBP 常见遗传变异的机制影响维生素D代谢。一个可能的机制或中介因素是 25OHD 的无血清部分（免费 25OHD 百分比）。药代动力学原理预测血清 DBP 浓度和 25OHD-DBP 结合亲和力将决定游离 25OHD 的百分比，这将影响组织的可用性和清除率 25OHD。本研究旨在证实这些预测。第一个研究目标是量化关联游离 25OHD 百分比和 25OHD 代谢清除率之间。我们将在一个大稳定的范围内追求这一目标 25OHD 清除的同位素示踪研究，包括黑人或白人种族的成年人。对于这个项目，血清将使用新型液相色谱法直接测量基线样品中的游离 25OHD 浓度 - 串联质谱法。我预计游离 25OHD 百分比与 25OHD 呈正相关代谢清除率并介导清除率与种族和 DBP 基因型的关联。第二个目标是量化 DBP 基因型与游离 25OHD 百分比以及血清 25OHD 和 PTH 的关联对补充维生素 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维生素 D 补充剂属于动脉粥样硬化多种族研究 (MESA)，这是一个由不同种族组成的队列美国成年人。将在基线和随访时测量游离 25OHD 的血清浓度。我期望游离 25OHD 百分比因 DBP 基因型而异，我假设 DBP 基因型影响 25OHD 清除率，因此改变了血清总 25OHD 对补充剂的反应，但不改变免费 25OHD 或 PTH 反应。总之，该项目将确定是否以及在多大程度上共同 DBP 的遗传变异与游离 25OHD 百分比、25OHD 清除率以及 25OHD 和 PTH 相关对补充维生素 D 的反应。预期结果包括对部分现象的机械解释血清总 25OHD 浓度与健康结果之间关联的异质性。知识这项工作产生的结果可能有助于发现更通用的维生素 D 状态生物标志物。这项目将为我提供与维生素 D 研究密切相关的概念和方法的指导培训生物学、营养生物标志物、新陈代谢和精准营养。作为大型临床研究的辅助，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奠定未来的方向。