Endocrine Abstracts (2007) 13 P275

Genetic variation at the CYP11B locus accounts for heritabilities of aldosterone excretion and 11-beta hydroxylase activity

E Marie Freel1, Helen Imrie2, Peter Avery2, Mary Ingram1, Bongani Mayosi3, Martin Farrall4, Hugh Watkins4, Robert Fraser1, Eleanor Davies1, John Connell1 & Bernard Keavney2


1GCRC, University of Glasgow, Glasgow, United Kingdom; 2University of Newcastle, Newcastle, United Kingdom; 3University of Cape Town, Cape Town, South Africa; 4University of Oxford, Oxford, United Kingdom.


Aldosterone is a key cardiovascular hormone: 15% of hypertensives have altered aldosterone regulation, defined by a raised ratio of aldosterone to renin. However, the causes of aldosterone excess are not understood. Polymorphic variation in the gene encoding aldosterone synthase (CYP11B2) is associated with hypertension, but the most robust phenotype is a relative reduction in efficiency of 11ß-hydroxylation (conversion of deoxycortisol to cortisol), which reflects function of the enzyme,11ß-hydroxylase, encoded by the adjacent gene (CYP11B1). To characterise better the genetic regulation of aldosterone synthesis we have used a family study to define heritability of steroid phenotypes and identify key genetic determinants.

We genotyped 6 polymorphisms in CYP11B2 and 3 in CYP11B1 in 248 nuclear families and measured urinary excretion rates of the major metabolites of aldosterone (THAldo), deoxycortisol (THS) total cortisol (F) and androgens in 573 subjects from 105 families. The efficiency of 11ß-hydroxylation, previously noted to be associated with CYP11B2, was assessed by the THS/F ratio.

THAldo and THS/F were highly heritable (P<0.0001). THAldo excretion and THS/F associated most strongly with polymorphisms in CYP11B1 (exon 1 and intron 3) (<0.001). THAldo excretion was closely correlated with F, androgens and THS/F (all P<0.001).

We have shown that aldosterone production is heritable, reflecting genetic regulation, and confirmed the heritability of THS/F, the index of 11ß-hydroxylation. The same polymorphisms in CYP11B1 account for variability in THAldo excretion and reduced efficiency of 11ß-hydroxylation, consistent with the hypothesis that a genetically determined change in 11ßhydroxylase efficiency leads to an increase in adrenal ACTH drive that, over years, amplifies aldosterone production. This is supported by strong correlations between THAldo and ACTH-dependent steroids (cortisol and androgens) and between THAldo and the index of 11ßhydroxylase efficiency. These data provide novel insights into the possible origins of aldosterone-associated hypertension.