Salvi, E. et al. (2017) Genome-wide and gene-based meta-analyses identify novel loci influencing blood pressure response to hydrochlorothiazide. Hypertension, 69(1), pp. 51-59. (doi: 10.1161/HYPERTENSIONAHA.116.08267) (PMID:27802415) (PMCID:PMC5145728)
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Abstract
This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure (BP) response to hydrochlorothiazide was performed in 1739 white hypertensives from 6 clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies, making it the largest study to date of its kind. No signals reached genome-wide significance (P<5×10−8), and the suggestive regions (P<10−5) were cross-validated in 2 black cohorts treated with hydrochlorothiazide. In addition, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in BP regulation, or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified 2 suggestive regulatory regions linked to gap junction protein α1 gene (GJA1) and forkhead box A1 gene (FOXA1), relevant for cardiovascular and kidney function. With the gene-based approach, we identified hydroxy-delta-5-steroid dehydrogenase, 3 β- and steroid δ-isomerase 1 gene (HSD3B1) as significantly associated with BP response (P<2.28×10−4). HSD3B1 encodes the 3β-hydroxysteroid dehydrogenase enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of BP response to hydrochlorothiazide, and using 2 different analytic approaches, we identified 3 novel loci influencing BP response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, which was not identified in the genome-wide meta-analysis because of high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna |
| Authors: | Salvi, E., Wang, Z., Rizzi, F., Gong, Y., McDonough, C. W., Padmanabhan, S., Hiltunen, T. P., Lanzani, C., Zaninello, R., Chittani, M., Bailey, K. R., Sarin, A.-P., Barcella, M., Melander, O., Chapman, A. B., Manunta, P., Kontula, K. K., Glorioso, N., Cusi, D., Dominiczak, A. F., Johnson, J. A., Barlassina, C., Boerwinkle, E., Cooper-DeHoff, R. M., and Turner, S. T. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
| Journal Name: | Hypertension |
| Publisher: | American Heart Association |
| ISSN: | 0194-911X |
| ISSN (Online): | 1524-4563 |
| Published Online: | 31 October 2016 |
| Copyright Holders: | Copyright © 2016 American Heart Association |
| First Published: | First published in Hypertension 2016 |
| Publisher Policy: | Reproduced in accordance with the copyright policy of the publisher |
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