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

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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.