The DASH-Sodium Trial: Genetic Determinants of Response

原发性高血压是几种遗传和环境因素相互作用的结果，包括营养因素。本研究的目的是确定调节BP对营养干预反应的基因。这项建议是作为饮食模式、钠摄入量和血压研究的修订延续提交的，以下称为饮食方法停止高血压(DASH)-钠试验。主要试验已经完成，并使用多个标准化的血压测量精确地确定了感兴趣的表型(对DASH饮食和减少钠摄入量的BP反应)。饮食摄入量在一项受控喂养研究中得到了控制。这项建议寻求通过利用现有的高质量数据进行基因关联研究，最大限度地发挥DASH-Na试验的价值。需要检验的假设是，基因构成通过以下一种或多种机制来调节DASH饮食的血压效应和钠摄入量的减少：1)影响血管张力；2)影响盐皮质激素对钠稳态的调节；以及3)对钠稳态的非经典调节。每个潜在的机制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、肾素和一氧化氮合酶；2)醛固酮合成酶、盐皮质激素受体和11-β羟基类固醇脱氢酶II；以及3)β2-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。每个个体都将接受这些候选基因中4-6个SNPs的基因分型，并进行关联测试。在探索性分析中，生化标记也将被用来定义中间表型。在这个具有独特特征的人群中使用最先进的基因技术，可能会增加我们对DASH饮食和减少钠摄入量降低血压的机制的理解(S)。最终，增加对这些机制的了解将导致改进预防和控制高血压的策略，包括营养和药物方面的。

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.