Hypertension (HTN) affects an estimated 60 million Americans, and is a major cause of morbidity and mortality. Diet, circulating molecules, and the interaction between genetics and environment may all impact the risk of developing HTN. Using prospective study designs (cohort and nested case-control studies), we propose to examine novel risk factors for incident HTN in three large independent cohorts. Based upon data that folate, other B vitamins, and methionine can influence endothelial function either directly or through effects on circulating homocysteine (Hey), we hypothesize that higher intakes of folate, vitamin B6, and vitamin B12 will reduce the risk of incident HTN, while higher methionine intake will increase the risk. Furthermore, we propose that higher circulating levels of Hey and soluble intercellular adhesion molecule-1 (sICAM) increase the risk of HTN. Given data demonstrating effects of vitamin D metabolites on the renin angiotensin system, we also propose that higher vitamin D levels will be associated with a lower risk of HTN. Finally, we hypothesize that genetic polymorphisms in MTHFR and eNOS will significantly modify the relation between folate and vitamin B12 and the risk of incident HTN, and that polymorphisms in the vitamin D receptor (VDR) will modify the association between vitamin D levels and HTN. The specific aims of this proposal are: (1) to assess the relation between novel and modifiable dietary factors and incident HTN;(2) to assess the relation between plasma levels of Hey, sICAM, and vitamin D metabolites and the subsequent development of HTN;and (3) to assess the interaction between MTHFR, eNOS, and VDR polymorphisms and specific environmental factors as they influence the risk of incident HTN. The candidate for this K08 award is John P. Forman, M.D., an Instructor in Medicine at Harvard Medical School, attending nephrologist at Brigham and Women's Hospital, and a Masters'Candidate in Epidemiology at Harvard School of Public Health. He is seeking further training and experience in advanced epidemiologic methods under the guidance of Gary C. Curhan, M.D., Sc.D., a well-known epidemiologist with an interest in HTN. This project proposal will provide the foundation for the candidate's future career as an independent and successful clinical scientist in HTN research. (End of Abstract)