Aldosterone is an important cardiovascular hormone. Around 15 % of hypertensives have alteration in aldosterone regulation, defined by a raised ratio of aldosterone to renin (ARR). Studies of CYP11B2, the aldosterone synthase gene, focus on a single nucleotide polymorphism in the 5'promotor region (-344 C/T). We have shown that the T allele is associated with increased urinary excretion and plasma levels of aldosterone and is more common amongst hypertensives with a raised ARR. In normotensives, this allele associates with raised basal and ACTH-stimulated levels of the 11-deoxysteroids, deoxycorticosterone and 11-deoxycortisol which are substrates for the enzyme 11beta-hydroxylase, encoded by the adjacent and homologous gene CYP11B1. We have examined the association between variation at this locus and adrenal steroid production in a pilot study of a population of subjects with essential hypertension.
CYP11B2 polymorphisms and urinary excretion of steroid metabolites were measured (by GCMS) in 511 unrelated hypertensives from the MRC BRIGHT study. This UK-wide study was designed to identify major genes contributing to essential hypertension and has extensive genetic and phenotypic data on > 2000 hypertensive sib-pairs.
The genotype frequencies for the CYP11B2 promoter polymorphism were consistent with other population studies (162TT; 275C/T; 74CC). Urinary aldosterone excretion was uninfluenced by genotype. However, the index of adrenal 11b-hydroxylation (ratio of tetrahydrocortisol / total cortisol excretion) was significantly elevated in the TT group (p<0.005) versus CC. This was especially apparent in males (p=0.002). There was no significant difference in cortisol excretion between the two groups (p=0.39).
These data are consistent with other observations that this variation in aldosterone synthase is associated with altered adrenal 11beta-hydroxylation, and support the hypothesis that increased ACTH drive to the adrenal maintains cortisol production at the expense of a slight increase in its immediate precursor in individuals with the T allele. The mechanism by which this can be associated with hypertension with a raised ARR remains speculative. More studies of genotype and steroid phenotype in hypertensives are indicated.
01 - 03 Nov 2004
Society for Endocrinology