The goal of this K99/R00 proposal is to build a mentored and independent research program for the applicant to comprehensively investigate the nutritional, biochemical, and genetic basis for vitamin D in the development of hypertension in women and men. Finding novel strategies to prevent hypertension, the most prevalent chronic disease in the U.S., is of critical public health importance. Accumulating evidence suggest that vitamin D is a promising nutritional agent for hypertension prevention. However, epidemiologic studies of vitamin D in relation to hypertension remain limited. Few prospective studies have examined the association between baseline circulating 25(OH)-vitamin D (25(OH)D), the biochemical marker of vitamin D status, and the subsequent risk of developing hypertension. Genetic epidemiologic studies to date have only tested a few polymorphisms in the vitamin D receptor (VDR) gene, among many genes in the vitamin D pathway, for association with blood pressure (BP) or hypertension. Moreover, the potential interaction of circulating vitamin D and vitamin D pathway gene polymorphisms on the risk of hypertension is largely unexplored. We will therefore investigate these associations in two large prospective cohorts: the Women's Health Study and the Physicians'Health Study. The applicant of this award has solid education and training background in cardiovascular disease (CVD) epidemiology and has access to rich research, facilities, and collaboration resources. The current goal of the applicant is to advance her knowledge and skills in genetic epidemiology research. Her long-term goal is to become an independent epidemiologist that investigates the biochemical and genetic markers relevant to the metabolism and functionality of nutritional factors in the development of hypertension and other CVD-related outcomes. During the K99 phase, the applicant will receive focused training in genetic epidemiology through didactic coursework, mentored research, seminars participation, and skill practice. The applicant will also conduct initial analyses of plasma 25(OH)D and genetic variants in vitamin D pathway (candidate genes including VDR, CYP27B1, CYP24A1, GC, RXRA, RXRB, and RXRG) in relation to BP and hypertension. During the R00 phase, the applicant will further extend her research to two specifically designed nested case-control studies of hypertension, assess prospective association between baseline plasma 25(OH)D and subsequent risk of hypertension, investigate the underlying mechanisms, as well as explore the potential gene-biomarker interactions. Findings from this study will substantially improve our understanding on the role of vitamin D in the development of hypertension and help optimize intervention strategy for hypertension prevention. Meanwhile the focused training and research together will offer the applicant a unique opportunity to integrate genetic epidemiology with her current research in CVD and nutritional epidemiology and greatly foster her career development to become an independent investigator on nutrition, metabolism, and genetics in the development of hypertension and CVD. PUBLIC HEALTH RELEVANCE: The proposed research project will substantially improve our understanding regarding the role of vitamin D in the development of hypertension, help identify high risk population and optimize intervention strategy, and provide basis for public health recommendations on the optimal vitamin D status for primary prevention of hypertension and other cardiovascular disease-related outcomes.