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

Xiaoying Gu, Dongfeng Gu, Jiang He, Dabeeru C. Rao, James E. Hixson, Jichun Chen, Jianxin Li, Jianfeng Huang, Xigui Wu, Treva K. Rice, Lawrence C. Shimmin, Tanika N. Kelly

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12 Scopus citations

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

Original languageEnglish
Pages (from-to)205-211
Number of pages7
JournalAmerican Journal of Hypertension
Volume31
Issue number2
DOIs
StatePublished - Feb 1 2018

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)

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