Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2007) 13 OC30

SFEBES2007 Oral Communications Neuroendocrinology, reproduction and cardiovascular (7 abstracts)

Consequences of variation in the CYP11B2 and CYP11B1 genes on hypothalamic-pituitary-adrenal axis activity

E Marie Freel 1 , Ann White 2 , Mary Ingram 1 , Robert Fraser 1 , Eleanor Davies 1 & John Connell 1

1GCRC, University of Glasgow, Glasgow, United Kingdom; 2University of Manchester, Manchester, United Kingdom.

Aldosterone is key in the development of hypertension. We have shown that a SNP (−344T) in the 5’ regulatory region (UTR) of the gene encoding aldosterone synthase (CYP11B2) was associated with aldosterone excess and high blood pressure. However, the most robust phenotype is altered adrenal 11-hydroxylation efficiency (deoxycortisol to cortisol); a step carried out by 11β-hydroxylase, encoded by the adjacent gene, CYP11B1. We proposed that the effects of CYP11B2 are explained by linkage disequilibrium (LD) across the CYP11B locus; the reduced adrenal 11-hydroxylation may lead to chronic resetting of the pituitary/adrenal axis, with chronically increased ACTH drive resulting in aldosterone excess. To support this we have already demonstrated high LD across this locus and identified 2 SNPs in the 5’ UTR of CYP11B1 (−1858G/T, −1888A/G) that associate with reduced transcriptional activity of this enzyme in vitro and altered 11-hydroxylation efficiency in vivo.

We examined HPA axis activity in hypertensive and normotensive individuals stratified according to genotype at CYP11B2 (−344T/C) and CYP11B1 (−1858G/T, −1888A/G). 56 subjects homozygous for CYP11B2 SNP (27 TT 12CC), and 38 homozygous for CYP11B1 SNPs (18 TTGG, 20 GGAA) were recruited. The effect of diurnal variation, dexamethasone suppression and ACTH stimulation on plasma aldosterone, cortisol and ACTH under controlled conditions was studied.

Subjects with SNPs associated with reduced 11-hydroxylation efficiency (−344T CYP11B2; TTGG CYP11B1) showed reduced inhibition of ACTH after dexamethasone (P=0.05) and altered cortisol/ACTH dynamic (decreased cortisol/ACTH ratio, P<0.02).

Variation in CYP11B2 and CYP11B1 associates with chronic upregulation of the HPA axis. These novel data support the suggestion that chronic aldosterone excess, in genetically susceptible individuals, may be a consequence of increased ACTH drive to the adrenal and identify novel molecular mechanisms that may lead to the development of hypertension within the general population.

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