Resequencing Epithelial Sodium Channel Genes Identifies Rare Variants Associated With Blood Pressure Salt-Sensitivity: The GenSalt Study. (19th September 2017)

• Record Type: Journal Article
• Authors: Gu, Xiaoying; Gu, Dongfeng; He, Jiang; Rao, Dabeeru C; Hixson, James E; Chen, Jichun; Li, Jianxin; Huang, Jianfeng; Wu, Xigui; Rice, Treva K; Shimmin, Lawrence C; Kelly, Tanika N
• Is Part Of: American journal of hypertension. Volume 31:Number 2(2018:Feb.)
• Page Start: 205
• Page End: 211
• Publication Date: 2017-09-19
• Subjects: blood pressure -- capillary-based sequencing -- dietary sodium -- epithelial 1 alpha subunit (SCNN1A) -- genetics -- hypertension -- mean arterial pressure -- rare variants -- salt sensitivity -- single nucleotide polymorphism -- sodium channel epithelial 1 beta subunit (SCNN1B) -- sodium channel epithelial 1 gamma subunit (SCNN1G); Hypertension -- Periodicals; 616.132005
• DOI: 10.1093/ajh/hpx169
• Languages: English
• ISSNs: 0895-7061

Abstract

Abstract: BACKGROUND: A resequencing study of renal epithelial sodium channel (ENaC) genes was conducted to identify rare variants associated with blood pressure (BP) salt-sensitivity. METHODS: The Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study was conducted among 1, 906 participants who underwent a 7-day low-sodium followed by a 7-day high-sodium feeding-study. The 300 most salt-sensitive and 300 most salt-resistant GenSalt participants were selected for the resequencing study. Three ENaC genes ( SCNN1A, SCNN1B, and SCNN1G ) were resequenced using capillary-based sequencing methods. Traditional burden tests were utilized to examine association between rare variants and BP salt-sensitivity. Associations of low-frequency and common variants were tested using single-marker analyses. RESULTS: Carriers of SCNN1A rare variants had a 0.52 [95% confidence interval (CI): 0.32–0.85] decreased odds of BP salt-sensitivity compared with noncarriers. Neither SCNN1B nor SCNN1G associated with salt-sensitivity of BP in rare variant analyses ( P = 0.65 and 0.48, respectively). In single-marker analyses, 3 independent common variants in SCNN1A, rs11614164, rs4764586, and rs3741914, associated with salt-sensitivity after Bonferroni correction ( P = 4.4 × 10 –4, 1.1 × 10 –8, and 1.3 × 10 –3 ). Each copy of the minor allele of rs4764586 was associated with a 1.36-fold (95% CI: 1.23–1.52) increased odds of salt-sensitivity, whereas each copy of the minor allele of rs11614164 and rs3741914 was associated with 0.68-fold (95% CI: 0.55–0.84) and 0.69-fold (95% CI: 0.54–0.86) decreased odds of salt-sensitivity, respectively. CONCLUSIONS: This study demonstrated for the first time a relationship between rare variants in the ENaC pathway and BP salt-sensitivity. Future replication and functional studies are needed to confirm the findings in this study. CLINICAL TRIAL REGISTRY: Trial Number NCT00721721