Common polymorphisms at the CYP17A1 locus associate with steroid phenotype: support for blood pressure genome-wide association study signals at this locus

Diver, L. A. et al. (2016) Common polymorphisms at the CYP17A1 locus associate with steroid phenotype: support for blood pressure genome-wide association study signals at this locus. Hypertension, 67(4), pp. 724-732. (doi: 10.1161/HYPERTENSIONAHA.115.06925) (PMID:26902494) (PMCID:PMC4789491)

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Genome-wide association studies implicate the CYP17A1 gene in human blood pressure regulation although the causative polymorphisms are as yet unknown. We sought to identify common polymorphisms likely to explain this association. We sequenced the CYP17A1 locus in 60 normotensive individuals and observed 24 previously identified single-nucleotide polymorphisms with minor allele frequency >0.05. From these, we selected, for further studies, 7 polymorphisms located ≤2 kb upstream of the CYP17A1 transcription start site. In vitro reporter gene assays identified 3 of these (rs138009835, rs2150927, and rs2486758) as having significant functional effects. We then analyzed the association between the 7 polymorphisms and the urinary steroid metabolites in a hypertensive cohort (n=232). Significant associations included that of rs138009835 with aldosterone metabolite excretion; rs2150927 associated with the ratio of tetrahydrodeoxycorticosterone to tetrahydrodeoxycortisol, which we used as an index of 17α-hydroxylation. Linkage analysis showed rs138009835 to be the only 1 of the 7 polymorphisms in strong linkage disequilibrium with the blood pressure–associated polymorphisms identified in the previous studies. In conclusion, we have identified, characterized, and investigated common polymorphisms at the CYP17A1 locus that have functional effects on gene transcription in vitro and associate with corticosteroid phenotype in vivo. Of these, rs138009835—which we associate with changes in aldosterone level—is in strong linkage disequilibrium with polymorphisms linked by genome-wide association studies to blood pressure regulation. This finding clearly has implications for the development of high blood pressure in a large proportion of the population and justifies further investigation of rs138009835 and its effects.

Item Type:Articles
Additional Information:LAD was supported by a College of Medical, Veterinary and Life Sciences Medical Research Council Doctoral Training Grant Scholarship (G0900185-1/1 ); FM and EMF were supported by Medical Research Council Fellowships; MJC and PBM acknowledge the National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts; MJC is a National Institute of Health Research Senior Investigator.
Glasgow Author(s) Enlighten ID:Friel, Mrs Elaine and Davies, Professor Eleanor and Dominiczak, Professor Anna and McManus, Dr Frances and Connell, Professor John and Alvarez-Madrazo, Dr Samantha and Diver, Miss Louise and Freel, Dr Marie and MacKenzie, Dr Scott and McClure, Dr John
Authors: Diver, L. A., MacKenzie, S. M., Fraser, R., McManus, F., Freel, E. M., Alvarez-Madrazo, S., McClure, J. D., Friel, E. C., Hanley, N. A., Dominiczak, A. F., Caulfield, M. J., Munroe, P. B., Connell, J. M., and Davies, E.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Hypertension
Publisher:American Heart Association
ISSN (Online):1524-4563
Published Online:22 February 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Hypertension 67(4):724-432
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
518771Doctoral Training Grant 2009-13Mary GoodmanMedical Research Council (MRC)G0900185-1/1VICE PRINCIPAL RESEARCH & ENTERPRISE