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

项目总结/摘要 维生素D结合蛋白（DBP）稳定维生素D代谢物的循环浓度，并调节 将其递送至组织。许多观察性研究将DBP的常见遗传变异与以下风险联系起来： 疾病其他研究发现，这些相同的遗传变异改变了血清总胆固醇和胆固醇之间的关系。 25-羟基维生素D（25 OHD）浓度和疾病结局。有趣的是，DBP的这些变体是 与祖先相关，可能是25种OHD疾病中部分种族异质性的基础。 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， 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。一个合理的机制或介导因素是25 OHD的血清游离分数 （游离25 OHD百分比）。药代动力学原理预测血清DBP浓度和25 OHD-DBP 结合亲和力将决定游离25 OHD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25 OHD和25 OHD代谢清除率之间的百分比。我们将在一个大的马厩里追求这个目标。 包括黑人或白色人种成人的25 OHD清除率的同位素示踪剂研究。在这个项目中，血清 将使用新型液相色谱法直接测量基线样本中的游离25 OHD浓度- 串联质谱法我预计游离25 OHD的百分比与25 OHD呈正相关 代谢清除率和介导的清除率与种族和DBP基因型。第二个目标是 定量DBP基因型与游离25 OHD百分比和血清25 OHD和PTH的相关性 补充维生素D的反应。我们将在一项维生素C的随机对照试验中实现这一目标。 补充维生素D嵌套在动脉粥样硬化的多种族研究（梅萨）中，这是一个种族多样的队列， 美国成年人了将在基线和随访时测量游离25 OHD的血清浓度。我预计 游离25 OHD的百分比因DBP基因型而异，我假设DBP基因型影响25 OHD 清除，因此改变血清总25 OHD补充反应，但不改变 游离25 OHD或PTH应答。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25 OHD、25 OHD清除率以及25 OHD和PTH相关 补充维生素D的反应。预期的结果包括一部分的机械解释， 血清总25 OHD浓度和健康结果之间的异质性。知识 这项工作产生的结果可能有助于发现更普遍的维生素D状态生物标志物。这 该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、代谢和精准营养。作为大型临床研究的辅助， 也将提高我的协作科学技能和种子未来的方向，我的研究事业在营养。

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.