Effect of variation in CYP11B1 and CYP11B2 on corticosteroid phenotype and hypothalamic-pituitary-adrenal axis activity in hypertensive and normotensive subjects

Freel, E.M., Ingram, M., Wallace, A.M., White, A., Fraser, R., Davies, E. and Connell, J.M.C. (2008) Effect of variation in CYP11B1 and CYP11B2 on corticosteroid phenotype and hypothalamic-pituitary-adrenal axis activity in hypertensive and normotensive subjects. Clinical Endocrinology, 68(5), pp. 700-706. (doi:10.1111/j.1365-2265.2007.03116.x)

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Publisher's URL: http://dx.doi.org/10.1111/j.1365-2265.2007.03116.x

Abstract

<b>Background</b>  Aldosterone is important in the development of hypertension. We have shown that a single nucleotide polymorphism (SNP) (–344T) in the 5′ regulatory region (UTR) of the gene encoding aldosterone synthase (CYP11B2) associates with aldosterone excess and hypertension as well as altered adrenal 11-hydroxylation efficiency (deoxycortisol to cortisol). This conversion is carried out by the enzyme 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. We have demonstrated high LD across this locus and identified two SNPs in the 5′ UTR ofCYP11B1 (–1859 G/T, –1889 A/G) that associate with reduced transcription in vitro and altered 11-hydroxylation efficiency in vivo. Accordingly, we hypothesized that the reduced adrenal 11-hydroxylation may lead to chronic resetting of the pituitary–adrenal axis, with chronically increased ACTH drive resulting in aldosterone excess.<p></p> <b>Methods</b>  To test this, we examined hypothalamic–pituitary–adrenal (HPA) axis activity in hypertensive and normotensive individuals stratified according to genotype at CYP11B2 (–344T/C) and CYP11B1 (–1859 G/T, –1889 A/G). Fifty-six subjects homozygous forCYP11B2 SNP (27 TT, 12 CC), and 38 homozygous for CYP11B1 SNPs (18 TTGG, 20 GGAA) were recruited. Diurnal variation and the effects of dexamethasone suppression and ACTH stimulation on plasma aldosterone, cortisol and ACTH under controlled conditions were studied.<p></p> <b>Results</b>  Subjects with SNPs associated with reduced 11-hydroxylation efficiency (–344T CYP11B2; TTGG CYP11B1) showed reduced inhibition of ACTH after dexamethasone (P = 0•05) and an altered cortisol–ACTH relationship (decreased cortisol–ACTH ratio, P < 0•02). The same individuals also demonstrated close correlations between plasma cortisol and aldosterone (–344T CYP11B2 r = 0•508,P < 0•004; TTGG CYP11B1 r = 0•563, P < 0•003) suggesting that there was common regulation (possibly ACTH) of these hormones in genetically susceptible subjects.<p></p> <b>Conclusions</b>  Variation in CYP11B2 and CYP11B1 associates with chronic up-regulation 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.<p></p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Davies, Professor Eleanor and Connell, Professor John and Freel, Dr Marie and Fraser, Prof Robert
Authors: Freel, E.M., Ingram, M., Wallace, A.M., White, A., Fraser, R., Davies, E., and Connell, J.M.C.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Clinical Endocrinology
Publisher:Society for Endocrinology
ISSN:0300-0664
ISSN (Online):1365-2265
Published Online:02 November 2007
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
392521Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874Institute of Cardiovascular and Medical Sciences
392522Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874Institute of Cardiovascular and Medical Sciences