The DASH-Sodium Trial: Genetic Determinants of Response

原发性高血压是多种遗传和环境因素（包括营养因素）相互作用的结果。 本研究的目的是确定调节BP对营养干预反应的基因。 该提案是作为膳食模式、钠摄入量和血压研究（以下简称为阻止高血压的饮食方法（DASH）-钠试验）的修订延续提交的。 主要试验已经完成，并且已经使用多个标准化血压测量精确地确定了感兴趣的表型（BP对DASH饮食和减少钠摄入的反应）。 饮食摄入量已在一项控制喂养研究中进行了操纵。 该提案旨在通过使用现有的高质量数据进行遗传关联研究，最大限度地发挥DASH-钠试验的价值。待检验的假设是，遗传组成通过以下一种或多种机制调节DASH饮食和减少钠摄入的BP效应：1）对血管张力的影响; 2）对盐皮质激素调节钠稳态的影响; 3）对钠稳态的非经典调节的影响。每种潜在机制都与一组候选基因相关：1）血管紧张素原、血管紧张素转换酶、血管紧张素II受体1型、肾素和一氧化氮合酶; 2）醛固酮合酶、盐皮质激素受体和11-β羟类固醇脱氢酶II型; 3）β 2-肾上腺素能受体、内收蛋白、鸟嘌呤核苷酸结合蛋白和激肽释放酶。 将对每个个体进行这些候选基因中的4-6个SNP的基因分型，并进行相关性测试。 在探索性分析中，还将使用生化标志物来定义中间表型。在这一具有独特特征的人群中使用最先进的遗传技术，可能会增加我们对DASH饮食和减少钠摄入量降低BP的机制的理解。 最终，对这些机制的进一步了解将导致改善高血压的预防和控制策略，包括营养和药理学。

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.