DESCRIPTION (provided by applicant): Impaired stress-induced pressure natriuresis is approximately twice as prevalent in black as in white youth. Salt, stress and genetics are three of the factors hypothesized to account for the difference. The proposed project will extend previous investigations in this area that focused on hormonal responses by identifying genetic predispositions responsible for impaired stress-induced pressure natriuresis. The overall goal is to determine the role of genes involved in the sodium-handling cascade in the renal tubules on dynamic regulation of sodium homeostasis and blood pressure under stress in blacks. These include five genes encoding the epithelial sodium channel (alpha ENaC, beta ENaC and gamma ENaC) and its accessory regulatory proteins such as serum glucocorticoid-inducible kinase (SGK-1) and neural precursor cell-expressed developmentally down-regulated 4 (Nedd4-2). The concerted Nedd4-SGK-ENaC interaction plays an important role in ENaC activity and tubular sodium handling. Environmental stress may promote sodium retention via intrinsic ENaC activity. Therefore, the primary aims are to test the following hypotheses in black youth;individuals with unfavorable genotypes or haplotypes compared to those without will show 1) a reduced stress-induced increase in urinary sodium excretion;2) delayed systolic blood pressure recovery following stress;and 3) greater plasma renin activity suppression (low-renin hypertension) during recovery following stress. The secondary aim is to explore gene-gene interactions among the five genes consisting of the ENaC pathway in relation to the three primary outcome variables. A total of 300 black youth will be studied which will include an equal number of boys and girls aged 15-19 yrs. All subjects will be tested with an extended stress protocol including a recovery period. Single nucleotide polymorphisms (SNPs) in the five genes will be systematically examined in these subjects using both direct (i.e., functional SNPs) and indirect (i.e., haplotype tagging SNPs) association approaches. Buccal cell DNA from the parents of these youth will be collected to facilitate (1) haplotype reconstruction and analyses and (2) transmission disequilibrium tests (TDTs). Classification and Regression Trees techniques will be used to explore possible gene-gene interactions. This proposed research will provide novel insight into the interactions between genetics, salt and environmental stress, and their contribution to the pathogenesis of essential hypertension. The project aims to investigate the influence of salt, stress and genes on the body's ability to release sodium. Understanding the connections between salt, stress and genetics will provide a fresh approach into evaluating risk factors for high blood pressure.
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