Clinical Endocrinology (2007) 67, 832–838 doi: 10.1111/j.1365-2265.2007.02971.x © 2007 The Authors 832 Journal compilation © 2007 Blackwell Publishing Ltd ORIGINAL ARTICLE Blackwell Publishing Ltd Phenotypic consequences of variation across the aldosterone synthase and 11-beta hydroxylase locus in a hypertensive cohort: data from the MRC BRIGHT Study E. M. Freel*, M. Ingram*, E. C. Friel*, R. Fraser*, M. Brown†, N. J. Samani‡, M. Caulfield§, P. Munroe§, M. Farrall¶, J. Webster**, D. Clayton†, A. F. Dominiczak*, E. Davies* and J. M. C. Connell* *Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, †Clinical Pharmacology and the Cambridge Institute of Medical Research, University of Cambridge, Addenbrooke’s Hospital, Cambridge, ‡Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, §Clinical Pharmacology and Barts and the London Genome Centre, William Harvey Research Institute, Barts and the London, Queen Mary’s School of Medicine, Charterhouse Square, London, ¶Nuffield Department of Clinical Medicine and Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, **Aberdeen Royal Infirmary, Aberdeen, UK Summary Background 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. Methods 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. Results 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 tetrahydrode- oxycortisol/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. Conclusions 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. (Received 12 March 2007; returned for revision 6 April 2007; finally revised 24 April 2007; accepted 22 May 2007) Introduction The importance of aldosterone excess in hypertension and cardio- vascular disease is increasingly recognized. Numerous studies, worldwide, report a high prevalence of primary aldosteronism (PA) in cohorts of hypertensive patients 1–7 mainly due to increasing use of the aldosterone to renin ratio (ARR) as a screening tool. Large- scale clinical trials confirm that aldosterone contributes significantly to the pathophysiology of cardiac failure 8 and that use of aldosterone- receptor antagonists as additional treatment in moderate to severe heart failure results in significant improvements in cardiovascular mortality. 9,10 Finally, data from the Framingham offspring popula- tion suggest that serum aldosterone levels predict hypertension risk; subjects with the highest levels of aldosterone (but still within the physiological range) are more likely to develop hypertension than individuals with lower levels of aldosterone. 11 Despite this recognition of the central importance of aldosterone, the underlying pathophysiology of aldosterone-associated hypertension remains obscure and more detailed analysis of the pattern of steroid production in hypertension is necessary to define more accurately Correspondence: Dr E. Marie Freel, Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, Scotland, UK. Tel.: (+44) 0141 330 3412; Fax: (+44) 0141 330 1763; E-mail: emf12k@clinmed.gla.ac.uk