Abstract P329: Resequencing of Renin-Angiotensin-Aldosterone-System Genes Identifies Rare Variants Associated with Blood Pressure Salt-Sensitivity: The GenSalt Study
Genetic association studies have revealed significant associations between common variants from renin-angiotensin-aldosterone system (RAAS) genes and blood pressure (BP) responses to dietary sodium intervention. However, the role of rare RAAS variants in salt-sensitivity remains unexplored. We conducted a resequencing study to identify rare functional variants associated with BP salt-sensitivity among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. The GenSalt study was conducted among 1,906 participants who underwent a 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium feeding-study (307.8 mmol sodium/day). We selected 300 GenSalt subjects with the highest and 300 GenSalt subjects with the lowest mean arterial pressure responses to the high sodium intervention to participate in the current resequencing study. Functional regions of seven RAAS genes, including ACE2, APLN, AGTR1, HSD11B1, HSD11B2, NR3C2, and RENBP were resequenced using the VariantSEQrTM system (Applied Biosystems; Foster City, CA). RAAS variants with minor allele frequencies less than 5% were collapsed according to gene and analyzed using the cohort allelic sums test (CAST). We identified significant associations between rare variants in the APLN, AGTR1, and HSD11B2 genes and BP salt-sensitivity, with p-values of 0.05, 0.03, and 0.03, respectively. Within the promoters, splice sites, exons, and 3’ untranslated regions of these 3 genes, we identified 17 rare APLN variants, 20 rare AGTR1 variants, and 19 rare HSD11B2 variants. Nine percent of GenSalt participants with high salt-sensitivity were carriers of at least one of the rare APLN variants, while only 4% of salt-resistant participants were carriers. In addition, approximately 17% of participants with high salt-sensitivity were carriers of rare AGTR1 variants compared to only 11% of salt-resistant subjects. Further, 8% of those who were highly salt-sensitive compared to only 4% of those who were salt-resistant were carriers of rare HSD11B2 variants. In summary, we provide the first evidence for a role of rare and potentially functional RAAS variants in BP salt-sensitivity. Validation study will be needed to confirm these findings.
- © 2013 by American Heart Association, Inc.