title: Effects of genetic variation in the aldosterone synthase (CYP11B2) gene on enzyme function.
abstract: OBJECTIVE
  Evidence suggests that high levels of aldosterone lead to hypertension and increased risk of cardiovascular disease. Around 15% of patients with essential hypertension have a raised aldosterone to renin ratio (ARR) suggesting that aldosterone production is inappropriately high in relation to its principal agonist angiotensin II. This may be due to increased activity of aldosterone synthase caused by genetic variation in the CYP11B2 gene. We screened the coding region of human CYP11B2 for genetic variants and tested their effects on function in vitro.
  
  
  METHODS
  Normotensive subjects (n = 69) were screened for sequence variants in the coding region of CYP11B2 by single-stranded conformation polymorphism (SSCP) analysis and sequencing. The effects of nonsynonymous variants on enzyme activity were assessed in JEG-3 cells transiently transfected with wild-type or variant expression plasmids. The conversion of the substrate 11-deoxycorticosterone (DOC) to corticosterone (B) and aldosterone was measured.
  
  
  RESULTS
  Twenty variants were detected in CYP11B2 and eight analysed functionally (Arg87Gly, Asn281Thr, Gly288Ser, Lys296Asn, Asp335Asn, Gln404Arg, Ala414Pro and His439Tyr). Corticosterone synthesis was unaltered and aldosterone synthesis reduced in variant Arg87Gly; Asn281Thr increased corticosterone and decreased aldosterone production; Gly288Ser increased corticosterone production and abolished aldosterone production; Lys296Asn reduced both corticosterone and aldosterone production; Asp335Asn increased corticosterone synthesis but did not affect aldosterone production. Variants Gln404Arg, Ala414Pro and His439Tyr showed increases in both corticosterone and aldosterone synthesis compared to the wild-type.
  
  
  CONCLUSIONS
  The study confirms the genetic variability of the CYP11B2 gene and provides us with additional valuable structure-function information.
authors: MRC Blood Pressure Group, BHF Cardiovascular Research Centre, 126 University Place, University of Glasgow, G12 8TA, UK.
authors: C D
authors: CD
authors: Holloway
authors: S M
authors: SM
authors: MacKenzie
authors: R
authors: R
authors: Fraser
authors: S
authors: S
authors: Miller
authors: M
authors: M
authors: Barr
authors: D
authors: D
authors: Wilkinson
authors: G H
authors: GH
authors: Forbes
authors: E
authors: E
authors: Friel
authors: J M C
authors: JM
authors: Connell
authors: E
authors: E
authors: Davies
mesh_terms: D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics* / Q000502:physiology*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA
chemical_list: D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D003345:Corticosterone