Genome-Wide Meta-Analysis of Blood Pressure Response to β1-Blockers: Results From ICAPS (International Consortium of Antihypertensive Pharmacogenomics Studies)

Sonal Singh, Helen R. Warren, Timo P. Hiltunen, Caitrin W. McDonough, Nihal El Rouby, Erika Salvi, Zhiying Wang, Tatiana Garofalidou, Frej Fyhrquist, Kimmo K. Kontula, Valeria Glorioso, Roberta Zaninello, Nicola Glorioso, Carl J. Pepine, Patricia B. Munroe, Stephan T. Turner, Arlene B. Chapman, Eric Boerwinkle, Julie A. Johnson, Yan GongRhonda M. Cooper-DeHoff

Research output: Contribution to journalReview article

3 Scopus citations

Abstract

Background: There exists a wide interindividual variability in blood pressure (BP) response to β1-blockers. To identify the genetic determinants of this variability, we performed a pharmacogenomic genome-wide meta-analysis of genetic variants influencing β1-blocker BP response. Methods and Results: Genome-wide association analysis for systolic BP and diastolic BP response to β1-blockers from 5 randomized clinical trials consisting of 1254 patients with hypertension of European ancestry were combined in meta-analysis and single nucleotide polymorphisms (SNPs) with P<10−4 were tested for replication in 2 independent randomized clinical trials of β1-blocker–treated patients of European ancestry (n=1552). Regions harboring the replicated SNPs were validated in a β1-blocker–treated black cohort from 2 randomized clinical trials (n=315). A missense SNP rs28404156 in BST1 was associated with systolic BP response to β1-blockers in the discovery meta-analysis (P=9.33×10−5, β=−3.21 mm Hg) and replicated at Bonferroni significance (P=1.85×10−4, β=−4.86 mm Hg) in the replication meta-analysis with combined meta-analysis approaching genome-wide significance (P=2.18×10−7). This SNP in BST1 is in linkage disequilibrium with several SNPs with putative regulatory functions in nearby genes, including CD38, FBXL5, and FGFBP1, all of which have been implicated in BP regulation. SNPs in this genetic region were also associated with BP response in the black cohort. Conclusions: Data from randomized clinical trials of 8 European ancestry and 2 black cohorts support the assumption that BST1 containing locus on chromosome 4 is associated with β1-blocker BP response. Given the previous associations of this region with BP, this is a strong candidate region for future functional studies and potential use in precision medicine approaches for BP management and risk prediction.

Original languageEnglish (US)
Article numbere013115
JournalJournal of the American Heart Association
Volume8
Issue number16
DOIs
StatePublished - Aug 20 2019

Keywords

  • blood pressure
  • hypertension
  • meta-analysis
  • pharmacogenomics
  • β-blocker
  • β-blocker

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Singh, S., Warren, H. R., Hiltunen, T. P., McDonough, C. W., El Rouby, N., Salvi, E., Wang, Z., Garofalidou, T., Fyhrquist, F., Kontula, K. K., Glorioso, V., Zaninello, R., Glorioso, N., Pepine, C. J., Munroe, P. B., Turner, S. T., Chapman, A. B., Boerwinkle, E., Johnson, J. A., ... Cooper-DeHoff, R. M. (2019). Genome-Wide Meta-Analysis of Blood Pressure Response to β1-Blockers: Results From ICAPS (International Consortium of Antihypertensive Pharmacogenomics Studies). Journal of the American Heart Association, 8(16), [e013115]. https://doi.org/10.1161/JAHA.119.013115