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

描述(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样本进行一项分两个阶段的全基因组关联(GWA)研究，定位和识别决定个人血压(BP)对膳食钠摄入量的反应的遗传变异。GenSalt是由NHLBI赞助的一项独特的家庭喂养研究，调查了来自中国北部农村地区658个家庭的3153名参与者。每个GenSalt家族都是通过人群BP筛查中发现的未经治疗的高血压前期或1期高血压的先证者确定的。饮食干预包括7天低钠喂养(51.3mmo1/d)、7天高钠喂养(307.8 mmo1/d)和7天高钠喂养加口服补钾(60 mmo1/d)，对1,906名先证者及其同胞、配偶和后代进行干预。其中，1,858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天和每3个干预期的最后3天进行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个人进行基于家庭的GWA研究，每个人至少有一个高度盐敏感的人。我们将使用Affymetrix对906,600个SNP进行基因分型。全基因组人类SNP阵列6.0，它提供了覆盖不同人群的几乎完整的基因组。我们将使用包含家族内依赖关系的混合模型方差分析来测试每个SNP与盐敏感性的关联。我们将根据来自GWA Stage-1分析和之前的全基因组连锁扫描的信息选择5,000个SNP。(2)通过对完成整个膳食钠干预的1,858名GenSalt参与者的全部5,000个SNP进行基因分型，进行一项基于家庭的第2阶段后续关联研究。我们将进行基于家庭的传递不平衡测试，以确定与盐敏感性最密切相关的250个SNP。(3)利用中国人(n=600)、白人(n=500)、黑人(n=360)和西班牙裔(n=300)的盐敏感表型数据和DNA标本，对250个SNP进行了多项研究的外部复制研究。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的高危人群，以及谁应该接受低钠饮食干预。此外，识别与BP盐敏感性相关的基因将有助于发现治疗高血压的新药物。这一领域的进展可以显著提高临床患者护理和全人群高血压预防的有效性。公共卫生相关性：拟议的研究将通过使用从盐敏感性遗传流行病学网络(GenSalt)的1858名参与者收集的表型数据和DNA样本进行全基因组关联研究，来检查基因变异和血压对膳食钠摄入量的反应之间的关系。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的高危人群，以及谁应该接受低钠饮食干预。此外，识别与血压盐敏感性相关的基因将有助于发现治疗高血压的新药物。

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.