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.
Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide / E. Salvi, Z. Wang, F. Rizzi, Y. Gong, C.W. Mcdonough, S. Padmanabhan, T.P. Hiltunen, C. Lanzani, R. Zaninello, M. Chittani, K.R. Bailey, A. Sarin, M. Barcella, O. Melander, A.B. Chapman, P. Manunta, K.K. Kontula, N. Glorioso, D. Cusi, A.F. Dominiczak, J.A. Johnson, C. Barlassina, E. Boerwinkle, R.M. Cooper-DeHoff, S.T. Turner. - In: HYPERTENSION. - ISSN 0194-911X. - 69:1(2017 Jan), pp. 51-59.
|Titolo:||Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide|
SALVI, ERIKA (Corresponding)
|Parole Chiave:||blood pressure response; diuretics; genome-wide association study; hydrochlorothiazide; hypertension; meta-analysis; pharmacogenomics|
|Settore Scientifico Disciplinare:||Settore MED/01 - Statistica Medica|
Settore BIO/18 - Genetica
Settore MED/03 - Genetica Medica
|Data di pubblicazione:||gen-2017|
|Data ahead of print / Data di stampa:||31-ott-2016|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.08267|
|Appare nelle tipologie:||01 - Articolo su periodico|