Resequencing study identifies rare renin-angiotensin-aldosterone system variants associated with blood pressure salt-sensitivity: The gensalt study

Tanika N. Kelly, Changwei Li, James E. Hixson, Dongfeng Gu, Dabeeru C. Rao, Jianfeng Huang, Treva K. Rice, Jichun Chen, Jie Cao, Jianxin Li, Christopher E. Anderson, Jiang He

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12 Scopus citations


BACKGROUND The role of rare variants in blood pressure (BP) salt-sensitivity is unknown. We conducted a resequencing study of the renin-angiotensin- aldosterone system (RAAS) to identify rare variants associated with BP salt-sensitivity among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. METHODS 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). The 300 most salt-sensitive and 300 most salt-resistant GenSalt participants were selected for the resequencing study. Seven RAAS genes were resequenced using capillary-based sequencing methods. Rare variants were tested for association with BP salt-sensitivity using traditional burden tests. Single-marker analyses were employed to test associations of low-frequency and common variants. RESULTS Aggregate rare variant analysis revealed an association of the RAAS pathway with BP salt-sensitivity. Carriers of rare RAAS variants had a 1.55-fold [95% confidence interval (CI): 1.15, 2.10] higher odds of saltsensitivity compared to noncarriers (P = 0.004), a finding which was significant after Bonferroni correction. A nominal association of the APLN gene with salt-sensitivity was also identified, with rare APLN variants conferring a 2.22-fold (95% CI: 1.05, 6.58) higher odds of salt-sensitivity (P = 0.03). Single-marker analyses did not identify variant-BP salt-sensitivity associations after Bonferroni adjustment. A nominal association of a low-frequency, missense RENBP variant was identified. Each minor allele of rs78377269 conferred a 2.21-fold (95% CI: 1.10, 4.42) increased odds of salt-sensitivity (P = 0.03). CONCLUSIONS This study presents of the first evidence of a contribution of rare RAAS variants to BP salt-sensitivity.

Original languageEnglish
Pages (from-to)495-501
Number of pages7
JournalAmerican Journal of Hypertension
Issue number5
StatePublished - May 1 2017


  • blood pressure
  • dietary sodium
  • genetics
  • hypertension
  • rare variants
  • resequencing
  • salt sensitivity


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