title: Resequencing Study Identifies Rare Renin-Angiotensin-Aldosterone System Variants Associated With Blood Pressure Salt-Sensitivity: The GenSalt Study.
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.
authors.affiliation: Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.
authors.forename: Tanika N
authors.initials: TN
authors.lastname: Kelly
authors.affiliation: Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia at Athens, Athens, Georgia, USA.
authors.forename: Changwei
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, Texas, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Hixson
authors.affiliation: Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, and Chinese National Center for Cardiovascular Disease Control and Research, Beijing, China.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Gu
authors.affiliation: Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Dabeeru C
authors.initials: DC
authors.lastname: Rao
authors.affiliation: Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, and Chinese National Center for Cardiovascular Disease Control and Research, Beijing, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Huang
authors.affiliation: Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Treva K
authors.initials: TK
authors.lastname: Rice
authors.affiliation: Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, and Chinese National Center for Cardiovascular Disease Control and Research, Beijing, China.
authors.forename: Jichun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, and Chinese National Center for Cardiovascular Disease Control and Research, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Cao
authors.affiliation: Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, and Chinese National Center for Cardiovascular Disease Control and Research, Beijing, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Anderson
authors.affiliation: Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.|Department of Epidemiology, School of Medicine, New Orleans, Louisiana, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: He
mesh_terms: D000328:Adult; D000073861:Apelin; D001794:Blood Pressure / Q000235:genetics*; D002238:Carbohydrate Epimerases / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D016009:Chi-Square Distribution; D002681:China / Q000453:epidemiology; D004039:Diet, Sodium-Restricted; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012084:Renin-Angiotensin System / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000009:adverse effects*; D013997:Time Factors
chemical_list: C115436:APLN protein, human; D000073861:Apelin; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D017673:Sodium Chloride, Dietary; D002238:Carbohydrate Epimerases; C498259:RENBP protein, human
keywords: blood pressure; dietary sodium; genetics; hypertension; rare variants; resequencing; salt sensitivity.