title: Association between aldosterone production and variation in the 11beta-hydroxylase (CYP11B1) gene.
abstract: BACKGROUND
  Variation in the region of chromosome 8 including the genes steroid 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) influences mineralocorticoid and glucocorticoid metabolism. However, the relative importance of polymorphisms in CYP11B1 and CYP11B2 in determining these phenotypes is unknown.
  
  
  OBJECTIVE
  Our objective was to investigate genetic influences of the CYP11B1 and CYP11B2 genes on mineralocorticoid metabolism.
  
  
  METHODS
  We measured 24-h urinary excretion of the key metabolites of the principal mineralocorticoids, glucocorticoids and androgens secreted by the adrenal cortex. We genotyped polymorphisms spanning the CYP11B1 and CYP11B2 genes, which together capture all common variations at the locus.
  
  
  METHODS
  Participants included 573 members of 105 British Caucasian families ascertained on a hypertensive proband.
  
  
  METHODS
  We assessed heritability of urinary tetrahydroaldosterone (THAldo) excretion and association of THAldo excretion with genotype.
  
  
  RESULTS
  The heritability of THAldo excretion was 52% (P < 10(-6)). There was significant association between THAldo and genotype at several of the CYP11B1/B2 polymorphisms. The strongest association was observed at the rs6387 (2803A/G) polymorphism in intron 3 of CYP11B1 (P = 0.0004). Association followed a codominant model with a 21% higher THAldo excretion per G allele. Genotype at rs6387 accounted for 2.1% of the total population variability of THAldo. We found significant association between THAldo excretion and urinary total androgen excretion, urinary tetrahydrodeoxycortisol level, and urinary cortisol metabolites (all P < 0.001).
  
  
  CONCLUSIONS
  Aldosterone synthesis is highly heritable and is affected by genotype at CYP11B1. Our findings support the hypothesis that genetically determined differences in 11-hydroxylation efficiency can have downstream effects on mineralocorticoid synthesis. Such effects may be of relevance to the development of low-renin essential hypertension.
authors.affiliation: Institute of Human Genetics, Central Parkway, Newcastle NE1 3BZ, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Imrie
authors.forename: Marie
authors.initials: M
authors.lastname: Freel
authors.forename: Bongani M
authors.initials: BM
authors.lastname: Mayosi
authors.forename: Eleanor
authors.initials: E
authors.lastname: Davies
authors.forename: Robert
authors.initials: R
authors.lastname: Fraser
authors.forename: Mary
authors.initials: M
authors.lastname: Ingram
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Avery
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.forename: Bernard
authors.initials: B
authors.lastname: Keavney
authors.forename: John M C
authors.initials: JM
authors.lastname: Connell
mesh_terms: D000450:Aldosterone / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000378:metabolism / Q000652:urine; D003350:Cortodoxone / Q000031:analogs & derivatives / Q000652:urine; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D013256:Steroids / Q000652:urine
chemical_list: D013256:Steroids; C013282:tetrahydroaldosterone; D000450:Aldosterone; C009412:tetrahydro-11-deoxycortisol; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D003350:Cortodoxone