Family-Based Genome-wide Association Study for Salt-Sensitivity of Blood Pressure

描述（由申请人提供）：拟议研究的总体目标是通过使用盐敏感性遗传流行病学网络（GenSalt）收集的数据和DNA样本进行两阶段全基因组关联（GWA）研究，定位和识别决定个体血压（BP）对饮食钠摄入量反应的遗传变异。GenSalt是一项独特的nhlbi赞助的家庭喂养研究，在中国北方农村地区的658个家庭中进行了3153名参与者。每个GenSalt家族通过先证者确定未经治疗的高血压前期或从人群BP筛查中确定的1期高血压。采用低钠喂养（51.3 mmol/d）、高钠喂养（307.8 mmol/d）和高钠喂养（60mmol /d）的饮食干预方法，对1906例先证及其兄弟姐妹、配偶和后代进行干预。其中，1858人（647个家庭）完成了整个膳食钠干预方案。在基线期间的每3天和3个干预期的最后3天分别进行3次血压测量。我们将追求以下具体目标：(1)对来自319个家庭的1000名个体进行以家庭为基础的GWA研究，每个家庭至少有一名高盐敏感个体。我们将使用Affymetrix对906,600个snp进行基因型分析。全基因组人类SNP阵列6.0，它提供了几乎完整的基因组覆盖不同的人群。我们将使用包含家庭依赖关系的方差混合模型分析来测试每个SNP与盐敏感性的关联。我们将根据GWA第一阶段分析和之前全基因组连锁扫描的信息选择5000个snp。(2)对完成整个膳食钠干预的1858名GenSalt参与者进行了一项基于家庭的2期随访关联研究，对所有5000个snp进行基因分型。我们将进行基于家庭的传播不平衡测试，以确定250个与盐敏感性最密切相关的snp。(3)利用现有的盐敏感性表型数据和DNA样本，对250个snp在多个研究中进行外部复制研究，研究对象包括中国人（n=600）、白人（n=500）、黑人（n=360）和西班牙裔（n=300）。这项拟议的研究具有重要的公共卫生和临床意义。建立基因变异和盐敏感性之间的关系将有助于确定高血压高危人群，以及哪些人应该接受低钠饮食干预。此外，确定与BP盐敏感性相关的基因将有助于发现新的高血压药物治疗方法。这一领域的进展可以显著提高临床患者护理和人群高血压预防的有效性。公共卫生相关性：拟议的研究将通过开展全基因组关联研究，利用从盐敏感性遗传流行病学网络（GenSalt）中收集的1858名参与者的表型数据和DNA样本，研究遗传变异和饮食钠摄入量对血压反应之间的关系。建立基因变异和盐敏感性之间的关系将有助于确定高血压高危人群，以及哪些人应该接受低钠饮食干预。此外，确定与血压盐敏感性相关的基因将有助于发现新的高血压药物治疗方法。

DESCRIPTION (provided by applicant): The overall objective of the proposed study is to localize and identify genetic variants which determine an individual's blood pressure (BP) response to dietary sodium intake by conducting a two-stage genome-wide association (GWA) study using the data and DNA specimens collected in the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt). GenSalt is a unique NHLBI-sponsored family feeding study conducted in 3,153 participants from 658 families living in rural areas of northern China. Each GenSalt family was ascertained through a proband with untreated pre-hypertension or stage-1 hypertension identified from a population BP screening. The dietary intervention which included a 7-day low-sodium feeding (51.3 mmol/day), a 7-day high-sodium feeding (307.8 mmol/day), and a 7-day high- sodium feeding with an oral potassium supplementation (60 mmol/day) was conducted among 1,906 probands and their sibs, spouses, and offspring. Of them, 1,858 individuals (647 families) completed the entire dietary sodium intervention protocol. Three BP measurements were obtained on each of 3- days during the baseline and the last 3-days of each of the 3 intervention periods. We will pursue the following specific aims: (1) Conduct a family-based GWA study among 1,000 individuals from 319 families, each with at least one highly salt-sensitive individual. We will genotype 906,600 SNPs using the Affymetrix. Genome-Wide Human SNP Array 6.0, which provides nearly complete genome coverage across different populations. We will test each SNP for association with salt-sensitivity using a mixed model analysis of variance incorporating dependencies within families. We will select 5,000 SNPs based on information from the GWA stage-1 analysis and from our previous genome-wide linkage scan. (2) Conduct a stage-2 family-based follow-up association study by genotyping all 5,000 SNPs in the 1,858 GenSalt participants who completed the entire dietary sodium intervention. We will perform family-based transmission disequilibrium tests to identify 250 SNPs most strongly associated with salt-sensitivity. (3) Conduct external replication studies of the 250 SNPs in multiple studies using existing salt-sensitivity phenotype data and DNA specimens in Chinese (n=600), Whites (n=500), Blacks (n=360), and Hispanics (n=300). The proposed study has important public health and clinical implications. Establishing a relationship between genetic variants and salt-sensitivity will help identify individuals at high risk for hypertension and who should receive a low sodium dietary intervention. In addition, identifying genes related to salt-sensitivity of BP should enable the discovery of new pharmaceutical treatment for hypertension. Advances in this area could significantly enhance the effectiveness of clinical patient care and population-wide prevention of hypertension. PUBLIC HEALTH RELEVANCE: The proposed study will examine the association between genetic variants and blood pressure responses to dietary sodium intake by conducting a genome-wide association study using the phenotype data and DNA specimens collected from 1,858 participants in the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt). Establishing a relationship between genetic variants and salt-sensitivity will help identify individuals at high risk for hypertension and who should receive a low sodium dietary intervention. In addition, identifying genes related to salt-sensitivity of blood pressure should enable the discovery of new pharmaceutical treatment for hypertension.