Molecular and Cellular Endocrinology 217 (2004) 243–247 The impact of polymorphisms in the gene encoding aldosterone synthase (CYP11B2) on steroid synthesis and blood pressure regulation John M.C. Connell ∗ , Robert Fraser, Scott M. MacKenzie, Elaine C. Friel, Mary C. Ingram, Christine D. Holloway, Eleanor Davies MRC Blood Pressure Group, Western Infirmary, Glasgow G11 6NT, UK Abstract The terminal stages in the synthesis of aldosterone and cortisol are catalysed by the enzymes aldosterone synthase and 11-hydroxylase respectively. We have previously reported that polymorphic variation in the 5 ′ promoter region (-344C/T) of the gene encoding aldosterone synthase (CYP11B2) is associated with increased aldosterone metabolite excretion and with hypertension associated with a raised aldosterone to renin ratio (ARR). Additionally, basal and ACTH-stimulated plasma levels of 11-deoxycortisol, the precursor of cortisol, are higher in subjects carrying the T-allelic variant. We have now identified in a family study (573 individuals from 105 extended families ascertained through a hypertensive proband) that excretion of the main metabolite of this steroid (tetrahydro-11-deoxycortisol, THS) is heritable (19.4%) and that the T-allele of CYP11B2 is more strongly associated with higher THS levels than the C-allele. Raised plasma and urinary levels of 11-deoxycortisol suggest that there is relative inefficiency of 11-hydroxylation in the zona fasciculata; the P450 enzyme responsible for this step is encoded by the gene CYP11B1, which is highly homologous with and adjacent to CYP11B2. The association of genetic variation in the promoter of CYP11B2 which, in the adrenal cortex, is only expressed in zona glomerulosa, and zona fasciculata 11-hydroxylation function is paradoxical. There may be linkage dys-equilibrium between this polymorphism and a quantitative trait locus (QTL) in CYP11B1. Chronic alteration of 11-hydroxylase activity may increase ACTH drive to the adrenal cortex, altering the regulation of aldosterone synthesis. This may explain, at least partly, the association between CYP11B2 polymorphisms and hypertension. © 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Aldosterone; Synthesis; Genetic; Hypertension 1. Introduction and results Aldosterone is a key cardiovascular hormone; blockade of the aldosterone receptor is an important therapeutic op- tion in patients with chronic heart failure (Pitt et al., 1999). Furthermore, aldosterone excess and its associated hyperten- sion cause significant tissue damage to the central nervous system, heart and kidney (Beevers et al., 1976; Brilla and Weber, 1992; Strandgaard and Paulson, 1994). Thus, factors that affect the regulation of aldosterone are of considerable importance in the development of cardiovascular disease. Aldosterone is synthesised from cholesterol in the zona glomerulosa of the adrenal cortex by a series of biochem- ical reactions, most of which represent residue-specific hydroxylation (White et al., 1992). These hydroxylations ∗ Corresponding author. Tel.: +44-141-211-2610; fax: +44-141-211-1763. E-mail address: j.connell@clinmed.gla.ac.uk (J.M.C. Connell). are catalysed by specific cytochrome P450 enzymes. The final steps in the production of aldosterone include the 11-hydroxylation of deoxycorticosterone to corticosterone, and the subsequent 18-hydroxylation and oxidation of cor- ticosterone to yield aldosterone. All of these steps are catal- ysed by a single enzyme, aldosterone synthase (Fig. 1). In the zona fasciculata of the human adrenal cortex, cortisol is pro- duced by 11-hydroxylation of 11-deoxycortisol, catalysed by 11-hydroxylase. The same enzyme also converts de- oxycorticosterone in the zona fasciculata to corticosterone. Thus, the late stages of cortisol and aldosterone synthe- sis are similar. Aldosterone synthase and 11-hydroxylase have similar primary amino acid sequences (>93% identity) (Mornet et al., 1989) differing only by a few key residues which confer the specific ability of aldosterone synthase to carry out the final hydroxylation and dehydration (oxida- tion) in aldosterone synthesis (Curnow et al., 1997). Their similarity of protein structure reflects a high degree of gene homology. Aldosterone synthase is encoded by 0303-7207/$ – see front matter © 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2003.10.025