This K01 application is in response to the Mentored Career Development Award to Promote Faculty Diversity/Re-entry in Biomedical Research (RFA-HL-10-012). The applicant seeks to develop an inter-disciplinary research career focused on the role of genetic susceptibility and environment in the developmental origins of adult cardiometabolic risk, building directly upon his previous training/experience in cardiovascular, reproductive, perinatal, nutritional and genetic epidemiology. Mounting evidence supports the developmental origins of cardiometabolic risk. Additionally, low vitamin D levels are associated with cardiometabolic risk factors. However, whether variations in vitamin D metabolism related genes and/or variations in genes differentially expressed in offspring with low vitamin D levels, account, in part, for the developmental origins of adult cardiometabolic risk is largely unknown. The applicant will use biologic specimens, clinical and examination data from mother and offspring diads from two well characterized study populations (the NIH funded Jerusalem Perinatal Study and the Omega Study) to examine vitamin D metabolism related genetic variations and cardiometabolic risk. Using tag-SNPs, the applicant will evaluate associations of common variations in a priori identified 5 candidate genes in vitamin D metabolism (LRP2, CUBN, CYP27B1, GC and VDR) with birth weight, and cardiometabolic risk factors, including obesity, insulin resistance, lipids and lipoproteins, and high blood pressure in young adults. In a pilot global whole blood gene expression study, using 1) cord blood and 2) peripheral blood from offspring with high/low vitamin D levels, the applicant will identify a set of novel candidate genes in fatty acid and glucose metabolism pathways related to vitamin D metabolism. The applicant then will examine associations of variations in these novel candidate genes in mothers and offspring with offspring birth weight and cardiometabolic risk in young adults. Secondarily, the applicant will evaluate whether variations in candidate/novel genes modify the associations of 25-hydroxy vitamin D to examine a set of hypothesis involving vitamin D metabolism related genetic risk factors and developmental origins of cardiometabolic risk. The candidate also has developed a mentoring framework with expertise in areas relevant to his research agenda that will help the candidate develop the capabilities needed to make unique contributions by conducting high quality and high impact interdisciplinary research related to gene-environment (nutrition) interactions and developmental origins of cardiometabolic diseases, levels with cardiometabolic risk. In sum, the findings from these studies will allow the candidate to examine a set of hypothesis involving vitamin D metabolism related genetic risk factors and developmental origins of cardiometabolic risk. The candidate also has developed a mentoring framework with expertise in areas relevant to his research agenda that will help the candidate develop the capabilities needed to make unique contributions by conducting high quality and high impact interdisciplinary research related to gene-environment (nutrition) interactions and developmental origins of cardiometabolic diseases. PUBLIC HEALTH RELEVANCE: While associations of adult cardiometabolic risk with low vitamin D levels have been well documented, the role of vitamin D metabolism related genetic variations in developmental origins of cardiometabolic risk is largely unknown. Among mother and offspring pairs of two well characterized studies, using genotyping, biomarker and gene expression measurements, we propose to investigate vitamin D related genetic variations and cardiometabolic risk. Study factors of developmental origins of cardiometabolic risk while the mentoring framework will enhance preparations of an underrepresented minority to become an independent cardiovascular disease epidemiologist in academia with the skills and capabilities to address further the developmental origins of adult cardiometabolic risk. Findings will address and/or generate testable hypothesis involving vitamin D related genetic risk. (End of Abstract)