Resequencing Epithelial Sodium Channel Genes Identifies Rare Variants Associated With Blood Pressure Salt-Sensitivity: The GenSalt Study

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.

Keywords: 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).