APEX1 regulation of aldosterone synthase gene transcription is disrupted by a common polymorphism in humans

McManus, F., Sands, W., Diver, L., MacKenzie, S. M. , Fraser, R., Davies, E. and Connell, J. M. (2012) APEX1 regulation of aldosterone synthase gene transcription is disrupted by a common polymorphism in humans. Circulation Research, 111(2), pp. 212-219. (doi: 10.1161/CIRCRESAHA.111.262931)

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Publisher's URL: http://dx.doi.org/10.1161/CIRCRESAHA.111.262931

Abstract

<b>Rationale:</b> The genetic mechanisms underlying hypertension are unclear, but relative aldosterone excess, present in ≈10% of hypertensive patients, is known to be a heritable trait. This phenotype associates with a T/C single nucleotide polymorphism (SNP) at position -344 of the aldosterone synthase gene (CYP11B2). However, deletion of this SNP has no effect on gene transcription. We have identified another T/C SNP at -1651, in tight linkage disequilibrium with the -344 SNP and here investigate its functional effect on CYP11B2 transcription.<p></p> <b>Objective:</b> We assessed the effect on transcriptional activity of the -1651 T/C SNP in vivo and in vitro and propose the mechanism by which transcriptional activity is altered.<p></p> <b>Methods and Results:</b> We demonstrated that the SNP at -1651 exerts significant allele-dependent effects on CYP11B2 transcription. We confirm binding of the transcriptional repressor APEX1 to -1651T, which is associated with reduced transcriptional activity in relation to the less strongly bound -1651C. We show that inhibiting APEX1 by small molecule inhibition or small interfering RNA (SiRNA) leads to increased CYP11B2 transcription. In addition, overexpression of APEX1 is associated with reduced transcriptional activity. Finally, we also show that -1651T associates with lower excretion rates of aldosterone metabolites in human subjects.<p></p> <b>Conclusions:</b> We conclude that APEX1 is a novel transcriptional repressor ofCYP11B2 and that differential APEX1 binding at -1651 of CYP11B2 results in altered gene expression. This mechanism may contribute to the observed relationship between CYP11B2 genotype and aldosterone phenotype in a subgroup of hypertensive patients.<p></p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Davies, Professor Eleanor and Connell, Professor John and MacKenzie, Dr Scott and Fraser, Prof Robert and McManus, Dr Frances and Diver, Miss Louise and Sands, Dr William
Authors: McManus, F., Sands, W., Diver, L., MacKenzie, S. M., Fraser, R., Davies, E., and Connell, J. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Circulation Research
Publisher:American Heart Association
ISSN:0009-7330
ISSN (Online):1524-4571
Published Online:31 May 2012
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
447141Variation in promoter function in CYP11B2 and regulation of aldosterone secretion in cardiovascular diseaseJohn ConnellMedical Research Council (MRC)G0601322SCHOOL OF MEDICINE