Phenotypic consequences of variation across the aldosterone synthase and 11-beta hydroxylase locus in a hypertensive cohort: data from the MRC BRIGHT Study

Freel, E.M. et al. (2007) Phenotypic consequences of variation across the aldosterone synthase and 11-beta hydroxylase locus in a hypertensive cohort: data from the MRC BRIGHT Study. Clinical Endocrinology, 67(6), pp. 832-838. (doi:10.1111/j.1365-2265.2007.02971.x)

Full text not currently available from Enlighten.

Publisher's URL: http://dx.doi.org/10.1111/j.1365-2265.2007.02971.x

Abstract

<b>Background</b>  Aldosterone is an important cardiovascular hormone; 15% of hypertensive subjects have alteration in aldosterone regulation, defined by a raised ratio of aldosterone to renin (ARR). Studies of the aldosterone synthase gene (CYP11B2) have focused on a single nucleotide polymorphism in the 5′promoter region (–344 C/T). In normotensive subjects, the T allele associates with raised levels of the 11-deoxysteroids, deoxycorticosterone and 11-deoxycortisol which are substrates for 11β-hydroxylase, encoded by the adjacent and homologous gene, CYP11B1. We have speculated that this altered 11β-hydroxylase efficiency leads to increased ACTH drive to the adrenal gland to maintain cortisol production and reported herein the association between the –344 C/T single nucleotide polymorphism (SNP) and adrenal steroid production in subjects with essential hypertension.<p></p> <b>Methods</b>  The CYP11B2–344 C/T polymorphism was genotyped and urinary excretion of adrenal steroid metabolites was measured (by GCMS) in 511 unrelated hypertensives from the Medical Research Council (MRC) British Genetics of Hypertension (BRIGHT) study.<p></p> <b>Results</b>  Thirty-five per cent of subjects were homozygous for the –344T allele whilst 16% were CC homozygotes. There was no difference in cortisol excretion rate between the two genotype groups but the index of adrenal 11β-hydroxylation (ratio of tetrahydrodeoxycortisol/total cortisol) was significantly higher in the TT group (P < 0•005) than in the CC group. Excretion rates of the major urinary metabolite of aldosterone (tetrahydroaldosterone) correlated strongly with the ACTH-regulated steroids, cortisol (r = 0•437, P < 0•0001) and total androgen metabolites (r = 0•4, P < 0•0001) in TT but not CC subjects.<p></p> <b>Conclusions</b>  Hypertensives homozygous for the –344 T allele of CYP11B2 demonstrate altered 11β-hydroxylase efficiency (CYP11B1); this is consistent with the hypothesis of a genetically determined increase in adrenal ACTH drive in these subjects. The correlation between excretion of aldosterone and cortisol metabolites and suggests that, in TT subjects, ACTH exerts an important common regulatory influence on adrenal corticosteroid production in subjects with hypertension.<p></p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Friel, Mrs Elaine and Davies, Professor Eleanor and Dominiczak, Professor Anna and Connell, Professor John and Freel, Dr Marie and Fraser, Prof Robert
Authors: Freel, E.M., Ingram, M., Friel, E.C., Fraser, R., Brown, M., Samani, N.J., Caulfield, M., Munroe, P., Farrall, M., Webster, J., Clayton, D., Dominiczak, A.F., 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:25 June 2007
Related URLs:

University Staff: Request a correction | Enlighten Editors: Update this record

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