Common polymorphisms in the CYP11B1 and CYP11B2 genes: evidence for a digenic influence on hypertension

Alvarez-Madrazo, S. et al. (2013) Common polymorphisms in the CYP11B1 and CYP11B2 genes: evidence for a digenic influence on hypertension. Hypertension, 61(1), pp. 232-239. (doi:10.1161/HYPERTENSIONAHA.112.200741)

Alvarez-Madrazo, S. et al. (2013) Common polymorphisms in the CYP11B1 and CYP11B2 genes: evidence for a digenic influence on hypertension. Hypertension, 61(1), pp. 232-239. (doi:10.1161/HYPERTENSIONAHA.112.200741)

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Publisher's URL: http://dx.doi.org/10.1161/HYPERTENSIONAHA.112.200741

Abstract

The locus encompassing the corticosteroidogenic genes CYP11B2 and CYP11B1 is of potential importance in essential hypertension. We analyzed the association of polymorphisms at this locus with risk of essential hypertension, using 2 white case-control collections for discovery (n=3340) and confirmation (n=2929). Single-marker and haplotype analyses were performed, with the CYP11B2 Intron 2 Conversion polymorphism showing strongest association with hypertension in both cohorts and in combined analysis (odds ratio=1.16, P=8.54×10(-5)). The CYP11B1 ACA haplotype associated with increased risk of hypertension relative to the alternative, GTC (odds ratio=1.11; P=7.4×10(-3)), whereas the CYP11B2 TWtC haplotype seemed protective relative to the contrasting CConvT (odds ratio=0.88, P=2.2×10(-3)). Analysis spanning the whole CYP11B1/CYP11B2 locus showed that haplotypes associated with raised risk of hypertension tend to coexist. Functional analysis of heterozygous human adrenal tissue demonstrated decreased CYP11B2 expression and increased CYP11B1 expression for those alleles associating with reduced risk of hypertension. These results confirm the hypertensive influence of this locus, with data suggesting a complex digenic mechanism whereby altered relative CYP11B1 and CYP11B2 gene expression could have a chronic effect on enzyme activity and corticosteroid synthesis.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Davies, Professor Eleanor and Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna and Connell, Professor John and Alvarez-Madrazo, Dr Samantha and MacKenzie, Dr Scott and Lee, Dr Wai Kwong
Authors: Alvarez-Madrazo, S., MacKenzie, S.M., Davies, E., Fraser, R., Lee, W.K., Brown, M., Caulfield, M.J., Dominiczak, A.F., Farrall, M., Lathrop, M., Hedner, T., Melander, O., Munroe, P.B., Samani, N., Stewart, P.M., Wahlstrand, B., Webster, J., Palmer, C.N.A., Padmanabhan, S., and Connell, J.M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Hypertension
Publisher:American Heart Association
ISSN:0194-911X
ISSN (Online):1524-4563
Published Online:12 November 2012
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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)G0400874RI CARDIOVASCULAR & MEDICAL SCIENCES
392522Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874RI CARDIOVASCULAR & MEDICAL SCIENCES