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

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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.