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

1 Citation (Scopus)

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

Fingerprint

Antihypertensive Agents
Meta-Analysis
Genome
Blood Pressure
Single Nucleotide Polymorphism
Randomized Controlled Trials
Pharmacogenomic Testing
Precision Medicine
Chromosomes, Human, Pair 4
Genome-Wide Association Study
Pharmacogenetics
Linkage Disequilibrium
Risk Management
Hypertension

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Genome-Wide Meta-Analysis of Blood Pressure Response to β1-Blockers : Results From ICAPS (International Consortium of Antihypertensive Pharmacogenomics Studies). / Singh, Sonal; Warren, Helen R.; Hiltunen, Timo P.; McDonough, Caitrin W.; El Rouby, Nihal; Salvi, Erika; Wang, Zhiying; Garofalidou, Tatiana; Fyhrquist, Frej; Kontula, Kimmo K.; Glorioso, Valeria; Zaninello, Roberta; Glorioso, Nicola; Pepine, Carl J.; Munroe, Patricia B.; Turner, Stephan T.; Chapman, Arlene B.; Boerwinkle, Eric; Johnson, Julie A.; Gong, Yan; Cooper-DeHoff, Rhonda M.

In: Journal of the American Heart Association, Vol. 8, No. 16, e013115, 20.08.2019.

Research output: Contribution to journalReview article

Singh, S, Warren, HR, Hiltunen, TP, McDonough, CW, El Rouby, N, Salvi, E, Wang, Z, Garofalidou, T, Fyhrquist, F, Kontula, KK, Glorioso, V, Zaninello, R, Glorioso, N, Pepine, CJ, Munroe, PB, Turner, ST, Chapman, AB, Boerwinkle, E, Johnson, JA, Gong, Y & Cooper-DeHoff, RM 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, vol. 8, no. 16, e013115. https://doi.org/10.1161/JAHA.119.013115
Singh, Sonal ; Warren, Helen R. ; Hiltunen, Timo P. ; McDonough, Caitrin W. ; El Rouby, Nihal ; Salvi, Erika ; Wang, Zhiying ; Garofalidou, Tatiana ; Fyhrquist, Frej ; Kontula, Kimmo K. ; Glorioso, Valeria ; Zaninello, Roberta ; Glorioso, Nicola ; Pepine, Carl J. ; Munroe, Patricia B. ; Turner, Stephan T. ; Chapman, Arlene B. ; Boerwinkle, Eric ; Johnson, Julie A. ; Gong, Yan ; Cooper-DeHoff, Rhonda M. / Genome-Wide Meta-Analysis of Blood Pressure Response to β1-Blockers : Results From ICAPS (International Consortium of Antihypertensive Pharmacogenomics Studies). In: Journal of the American Heart Association. 2019 ; Vol. 8, No. 16.
@article{d4bd66adf71243ebbd05002a48f7073d,
title = "Genome-Wide Meta-Analysis of Blood Pressure Response to β1-Blockers: Results From ICAPS (International Consortium of Antihypertensive Pharmacogenomics Studies)",
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.",
keywords = "blood pressure, hypertension, meta-analysis, pharmacogenomics, β-blocker, β-blocker",
author = "Sonal Singh and Warren, {Helen R.} and Hiltunen, {Timo P.} and McDonough, {Caitrin W.} and {El Rouby}, Nihal and Erika Salvi and Zhiying Wang and Tatiana Garofalidou and Frej Fyhrquist and Kontula, {Kimmo K.} and Valeria Glorioso and Roberta Zaninello and Nicola Glorioso and Pepine, {Carl J.} and Munroe, {Patricia B.} and Turner, {Stephan T.} and Chapman, {Arlene B.} and Eric Boerwinkle and Johnson, {Julie A.} and Yan Gong and Cooper-DeHoff, {Rhonda M.}",
year = "2019",
month = "8",
day = "20",
doi = "10.1161/JAHA.119.013115",
language = "English (US)",
volume = "8",
journal = "Journal of the American Heart Association",
issn = "2047-9980",
publisher = "Wiley-Blackwell",
number = "16",

}

TY - JOUR

T1 - Genome-Wide Meta-Analysis of Blood Pressure Response to β1-Blockers

T2 - Results From ICAPS (International Consortium of Antihypertensive Pharmacogenomics Studies)

AU - Singh, Sonal

AU - Warren, Helen R.

AU - Hiltunen, Timo P.

AU - McDonough, Caitrin W.

AU - El Rouby, Nihal

AU - Salvi, Erika

AU - Wang, Zhiying

AU - Garofalidou, Tatiana

AU - Fyhrquist, Frej

AU - Kontula, Kimmo K.

AU - Glorioso, Valeria

AU - Zaninello, Roberta

AU - Glorioso, Nicola

AU - Pepine, Carl J.

AU - Munroe, Patricia B.

AU - Turner, Stephan T.

AU - Chapman, Arlene B.

AU - Boerwinkle, Eric

AU - Johnson, Julie A.

AU - Gong, Yan

AU - Cooper-DeHoff, Rhonda M.

PY - 2019/8/20

Y1 - 2019/8/20

N2 - 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.

AB - 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.

KW - blood pressure

KW - hypertension

KW - meta-analysis

KW - pharmacogenomics

KW - β-blocker

KW - β-blocker

UR - http://www.scopus.com/inward/record.url?scp=85072150663&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072150663&partnerID=8YFLogxK

U2 - 10.1161/JAHA.119.013115

DO - 10.1161/JAHA.119.013115

M3 - Review article

C2 - 31423876

AN - SCOPUS:85072150663

VL - 8

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 16

M1 - e013115

ER -