Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide

Erika Salvi; Zhiying Wang; Federica Rizzi; Yan Gong; Caitrin W McDonough; Sandosh Padmanabhan; Timo P Hiltunen; Chiara Lanzani; Roberta Zaninello; Martina Chittani; Kent R Bailey; Antti-Pekka Sarin; Matteo Barcella; Olle Melander; Arlene B Chapman; Paolo Manunta; Kimmo K Kontula; Nicola Glorioso; Daniele Cusi; Anna F Dominiczak; Julie A Johnson; Cristina Barlassina; Eric Boerwinkle; Rhonda M Cooper-DeHoff; Stephen T Turner

doi:10.1161/HYPERTENSIONAHA.116.08267

Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide

Hypertension. 2017 Jan;69(1):51-59. doi: 10.1161/HYPERTENSIONAHA.116.08267. Epub 2016 Oct 31.

Authors

Erika Salvi¹, Zhiying Wang², Federica Rizzi², Yan Gong², Caitrin W McDonough², Sandosh Padmanabhan², Timo P Hiltunen², Chiara Lanzani², Roberta Zaninello², Martina Chittani², Kent R Bailey², Antti-Pekka Sarin², Matteo Barcella², Olle Melander², Arlene B Chapman², Paolo Manunta², Kimmo K Kontula², Nicola Glorioso², Daniele Cusi², Anna F Dominiczak², Julie A Johnson², Cristina Barlassina², Eric Boerwinkle², Rhonda M Cooper-DeHoff², Stephen T Turner²

Affiliations

¹ From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.). erika.salvi@unimi.it.
² From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).

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.

Keywords: blood pressure response; diuretics; genome-wide association study; hydrochlorothiazide; hypertension; meta-analysis; pharmacogenomics.

Publication types

Meta-Analysis
Review
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Diuretics / pharmacology
Genome-Wide Association Study / methods*
Humans
Hydrochlorothiazide / pharmacology*
Hypertension* / drug therapy
Hypertension* / genetics
Hypertension* / physiopathology

Substances

Diuretics
Hydrochlorothiazide

Abstract

Publication types

MeSH terms

Substances

Grants and funding