The DASH-Sodium Trial: Genetic Determinants of Response

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Essential hypertension results from the interaction of several genetic and environmental factors, including nutritional factors. The purpose of this study is to identify genes that modulate BP response to nutritional interventions. This proposal is being submitted as an amended continuation of the Dietary Patterns, Sodium Intake, and Blood Pressure study, hereafter referred to as the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial. The main trial is completed, and the phenotypes of interest (BP response to DASH diet and to reduced sodium intake) have been precisely determined using multiple, standardized blood pressure measurements. Dietary intake has been manipulated in a controlled feeding study. This proposal seeks to maximize the value of the DASH-Sodium trial by using existing high-quality data for a genetic association study. The hypothesis to be tested is that genetic makeup modulates the BP effects of DASH diet and reduced sodium intake through one or more of the following mechanisms: 1) effects on vascular tone; 2) effects on mineralocorticoid regulation of sodium homeostasis; and 3) effects on non-classical regulation of sodium homeostasis. Each potential mechanism is associated with a group of candidate genes: 1) angiotensinogen, angiotensin converting enzyme, angiotensin II receptor type 1, renin, and nitric oxide synthase; 2) aldosterone synthase, mineralocorticoid receptor, and 11-beta hydroxysteroid dehydrogenase type II; and 3) beta2-adrenergic receptor, adducin, guanine nucleotide binding protein, and kallikrein. Each individual will be genotyped for 4-6 SNPs in each of these candidate genes, and tests for association will be performed. Biochemical markers will also be used to define intermediate phenotypes in exploratory analyses. The use of state-of-the-art genetic techniques in this uniquely- characterized population will potentially increase our understanding of the mechanism(s) by which DASH diet and reduced sodium intake lower BP. Ultimately, increased understanding of these mechanisms will lead to improved strategies for prevention and control, both nutritional and pharmacologic, of high BP.