Resequencing Study Identifies Rare Renin-Angiotensin-Aldosterone System Variants Associated With Blood Pressure Salt-Sensitivity: The GenSalt Study

Am J Hypertens. 2017 May 1;30(5):495-501. doi: 10.1093/ajh/hpx004.

Abstract

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 salt-sensitivity 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. Clinical Trial RegistryTrial Number: NCT00721721.

Keywords: blood pressure; dietary sodium; genetics; hypertension; rare variants; resequencing; salt sensitivity..

MeSH terms

  • Adult
  • Apelin
  • Blood Pressure / genetics*
  • Carbohydrate Epimerases / genetics
  • Carrier Proteins / genetics
  • Chi-Square Distribution
  • China / epidemiology
  • Diet, Sodium-Restricted
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Humans
  • Hypertension / diagnosis
  • Hypertension / epidemiology
  • Hypertension / genetics*
  • Hypertension / physiopathology
  • Intercellular Signaling Peptides and Proteins / genetics
  • Linear Models
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Odds Ratio
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Renin-Angiotensin System / genetics*
  • Risk Assessment
  • Risk Factors
  • Sodium Chloride, Dietary / administration & dosage
  • Sodium Chloride, Dietary / adverse effects*
  • Time Factors

Substances

  • APLN protein, human
  • Apelin
  • Carrier Proteins
  • Intercellular Signaling Peptides and Proteins
  • Sodium Chloride, Dietary
  • Carbohydrate Epimerases
  • RENBP protein, human

Associated data

  • ClinicalTrials.gov/NCT00721721