title: Common variants of the beta and gamma subunits of the epithelial sodium channel and their relation to plasma renin and aldosterone levels in essential hypertension.
abstract: BACKGROUND
  Rare mutations of the epithelial sodium channel (ENaC) result in the monogenic hypertension form of Liddle's syndrome. We decided to screen for common variants in the ENaC beta and gamma subunits in patients with essential hypertension and to relate their occurrence to the activity of circulating renin-angiotensin-aldosterone system.
  
  
  METHODS
  Initially, DNA samples from 27 patients with low renin/low aldosterone hypertension were examined. The DNA variants were subsequently screened for in 347 patients with treatment-resistant hypertension, 175 male subjects with documented long-lasting normotension and 301 healthy Plasma renin and aldosterone levels were measured under baseline conditions and during postural and captopril challenge tests.
  
  
  RESULTS
  Two commonly occurring betaENaC variants (G589S and a novel intronic i12-17CT substitution) and one novel gammaENaC variant (V546I) were detected. One of these variants occurred in a heterozygous form in 32 patients, a prevalence (9.2%) significantly higher than that in normotensive males (2.9%, p = 0.007) and blood donors (3.0%, p = 0.001). betaENaC i12-17CT was significantly more prevalent in the hypertension group than in the two control groups combined (4.6% vs. 1.1%, p = 0.001). When expressed in Xenopus oocytes, neither of the two ENaC amino acid-changing variants showed a significant difference in activity compared with ENaC wild-type. No direct evidence for a mRNA splicing defect could be obtained for the betaENaC intronic variant. The ratio of daily urinary potassium excretion to upright and mean (of supine and upright values) plasma renin activity was higher in variant allele carriers than in non-carriers (p = 0.034 and p = 0.048).
  
  
  CONCLUSIONS
  At least 9% of Finnish patients with hypertension admitted to a specialized center carry genetic variants of beta and gammaENaC, a three times higher prevalence than in the normotensive individuals or in random healthy controls. Patients with the variant alleles showed an increased urinary potassium excretion rate in relation to their renin levels.
authors.affiliation: Department of Medicine, University of Helsinki, and Biomedicum Helsinki, University of Helsinki, 00290 Helsinki, Finland. tuula.hannila-handelberg@hus.fi
authors.forename: Tuula
authors.initials: T
authors.lastname: Hannila-Handelberg
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
authors.forename: Ilkka
authors.initials: I
authors.lastname: Tikkanen
authors.forename: Tuula
authors.initials: T
authors.lastname: Tikkanen
authors.forename: Frej
authors.initials: F
authors.lastname: Fyhrquist
authors.forename: Karri
authors.initials: K
authors.lastname: Helin
authors.forename: Heidi
authors.initials: H
authors.lastname: Fodstad
authors.forename: Kirsi
authors.initials: K
authors.lastname: Piippo
authors.forename: Helena E
authors.initials: HE
authors.lastname: Miettinen
authors.forename: Jarmo
authors.initials: J
authors.lastname: Virtamo
authors.forename: Tom
authors.initials: T
authors.lastname: Krusius
authors.forename: Seppo
authors.initials: S
authors.lastname: Sarna
authors.forename: Ivan
authors.initials: I
authors.lastname: Gautschi
authors.forename: Laurent
authors.initials: L
authors.lastname: Schild
authors.forename: Timo P
authors.initials: TP
authors.lastname: Hiltunen
mesh_terms: D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000097:blood*; D000483:Alleles; D053503:Epithelial Sodium Channels; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D021122:Protein Subunits / Q000235:genetics; D012083:Renin / Q000097:blood*; D012084:Renin-Angiotensin System; D017422:Sequence Analysis, DNA; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D053503:Epithelial Sodium Channels; D021122:Protein Subunits; C507048:SCNN1B protein, human; D015222:Sodium Channels; D000450:Aldosterone; D012083:Renin