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血压对营养干预反应的基因。该提案是作为饮食模式、钠摄入量和血压研究的修订延续提交的，以下简称为饮食方法来阻止高血压(DASH)-钠试验。主要试验已经完成，相关表型（对DASH饮食和减少钠摄入量的血压反应）已经通过多种标准化血压测量精确确定。在一项控制喂养研究中，饮食摄入量被控制。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来最大化DASH-Sodium试验的价值。待验证的假设是，基因组成通过以下一种或多种机制调节DASH饮食和钠摄入量减少对血压的影响：1)对血管张力的影响；2)盐皮质激素对钠稳态的调节作用；3)非经典调控对钠稳态的影响。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)醛固酮合成酶、矿糖皮质激素受体、11- β羟类固醇脱氢酶II型；3) β -肾上腺素能受体，内收蛋白，鸟嘌呤核苷酸结合蛋白，和钾激肽。每个个体将在每个候选基因中进行4-6个snp的基因分型，并进行相关性测试。生化标记也将用于在探索性分析中定义中间表型。在这一具有独特特征的人群中使用最先进的遗传技术，将有可能增加我们对DASH饮食和减少钠摄入量降低血压的机制的理解。最终，增加对这些机制的理解将导致改善预防和控制高血压的策略，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.