Genetic variants associated with uncontrolled blood pressure on thiazide diuretic/β-blocker combination therapy in the PEAR (Pharmacogenomic Evaluation Of Antihypertensive Responses) and INVEST (International Verapamil-SR Trandolapril Study) trials

Oyunbileg Magvanjav, Yan Gong, Caitrin W. McDonough, Arlene B. Chapman, Stephen T. Turner, John G. Gums, Kent R. Bailey, Eric Boerwinkle, Amber L. Beitelshees, Toshihiro Tanaka, Michiaki Kubo, Carl J. Pepine, Rhonda M. Cooper-DeHoff, Julie A. Johnson

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Abstract

Background--The majority of hypertensive individuals require combination antihypertensive therapy to achieve adequate blood pressure (BP) control. This study aimed to identify genetic variants associated with uncontrolled BP on combination therapy with a thiazide diuretic and a β-blocker. Methods and Results--A genome-wide association study of uncontrolled BP on combination therapy was conducted among 314 white participants of the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) trial. Multivariable logistic regression analysis was used. Genetic variants meeting a suggestive level of significance (P < 1.0E-05) were tested for replication in an external cohort, INVEST (International Verapamil-SR Trandolapril study). We also examined genome-wide variant associations with systolic and diastolic BP response on combination therapy and tested for replication. We discovered a single nucleotide polymorphism, the rs261316 major allele, at chromosome 15 in the gene ALDH1A2 associated with an increased odds of having uncontrolled BP on combination therapy (odds ratio: 2.56, 95% confidence interval, 1.69-3.88, P=8.64E-06). This single nucleotide polymorphism replicated (odds ratio: 1.86, 95% confidence interval, 1.35-2.57, P=0.001) and approached genome-wide significance in the metaanalysis between discovery and replication cohorts (odds ratio: 2.16, 95% confidence interval, 1.63-2.86, P=8.60E-08). Other genes in the region surrounding rs261316 (ALDH1A2) include AQP9 and LIPC. Conclusions--A single nucleotide polymorphism in the gene ALDH1A2 may be associated with uncontrolled BP following treatment with a thiazide diuretic/β-blocker combination.

Original languageEnglish
Article numbere006522
JournalJournal of the American Heart Association
Volume6
Issue number11
DOIs
Publication statusPublished - 01-11-2017

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trandolapril
Sodium Chloride Symporter Inhibitors
Pharmacogenetics
Verapamil
Antihypertensive Agents
Blood Pressure
Single Nucleotide Polymorphism
Odds Ratio
Confidence Intervals
Therapeutics
Genome
Genes
Chromosomes, Human, Pair 15
Genome-Wide Association Study

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Magvanjav, Oyunbileg ; Gong, Yan ; McDonough, Caitrin W. ; Chapman, Arlene B. ; Turner, Stephen T. ; Gums, John G. ; Bailey, Kent R. ; Boerwinkle, Eric ; Beitelshees, Amber L. ; Tanaka, Toshihiro ; Kubo, Michiaki ; Pepine, Carl J. ; Cooper-DeHoff, Rhonda M. ; Johnson, Julie A. / Genetic variants associated with uncontrolled blood pressure on thiazide diuretic/β-blocker combination therapy in the PEAR (Pharmacogenomic Evaluation Of Antihypertensive Responses) and INVEST (International Verapamil-SR Trandolapril Study) trials. In: Journal of the American Heart Association. 2017 ; Vol. 6, No. 11.
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title = "Genetic variants associated with uncontrolled blood pressure on thiazide diuretic/β-blocker combination therapy in the PEAR (Pharmacogenomic Evaluation Of Antihypertensive Responses) and INVEST (International Verapamil-SR Trandolapril Study) trials",
abstract = "Background--The majority of hypertensive individuals require combination antihypertensive therapy to achieve adequate blood pressure (BP) control. This study aimed to identify genetic variants associated with uncontrolled BP on combination therapy with a thiazide diuretic and a β-blocker. Methods and Results--A genome-wide association study of uncontrolled BP on combination therapy was conducted among 314 white participants of the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) trial. Multivariable logistic regression analysis was used. Genetic variants meeting a suggestive level of significance (P < 1.0E-05) were tested for replication in an external cohort, INVEST (International Verapamil-SR Trandolapril study). We also examined genome-wide variant associations with systolic and diastolic BP response on combination therapy and tested for replication. We discovered a single nucleotide polymorphism, the rs261316 major allele, at chromosome 15 in the gene ALDH1A2 associated with an increased odds of having uncontrolled BP on combination therapy (odds ratio: 2.56, 95{\%} confidence interval, 1.69-3.88, P=8.64E-06). This single nucleotide polymorphism replicated (odds ratio: 1.86, 95{\%} confidence interval, 1.35-2.57, P=0.001) and approached genome-wide significance in the metaanalysis between discovery and replication cohorts (odds ratio: 2.16, 95{\%} confidence interval, 1.63-2.86, P=8.60E-08). Other genes in the region surrounding rs261316 (ALDH1A2) include AQP9 and LIPC. Conclusions--A single nucleotide polymorphism in the gene ALDH1A2 may be associated with uncontrolled BP following treatment with a thiazide diuretic/β-blocker combination.",
author = "Oyunbileg Magvanjav and Yan Gong and McDonough, {Caitrin W.} and Chapman, {Arlene B.} and Turner, {Stephen T.} and Gums, {John G.} and Bailey, {Kent R.} and Eric Boerwinkle and Beitelshees, {Amber L.} and Toshihiro Tanaka and Michiaki Kubo and Pepine, {Carl J.} and Cooper-DeHoff, {Rhonda M.} and Johnson, {Julie A.}",
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Genetic variants associated with uncontrolled blood pressure on thiazide diuretic/β-blocker combination therapy in the PEAR (Pharmacogenomic Evaluation Of Antihypertensive Responses) and INVEST (International Verapamil-SR Trandolapril Study) trials. / Magvanjav, Oyunbileg; Gong, Yan; McDonough, Caitrin W.; Chapman, Arlene B.; Turner, Stephen T.; Gums, John G.; Bailey, Kent R.; Boerwinkle, Eric; Beitelshees, Amber L.; Tanaka, Toshihiro; Kubo, Michiaki; Pepine, Carl J.; Cooper-DeHoff, Rhonda M.; Johnson, Julie A.

In: Journal of the American Heart Association, Vol. 6, No. 11, e006522, 01.11.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic variants associated with uncontrolled blood pressure on thiazide diuretic/β-blocker combination therapy in the PEAR (Pharmacogenomic Evaluation Of Antihypertensive Responses) and INVEST (International Verapamil-SR Trandolapril Study) trials

AU - Magvanjav, Oyunbileg

AU - Gong, Yan

AU - McDonough, Caitrin W.

AU - Chapman, Arlene B.

AU - Turner, Stephen T.

AU - Gums, John G.

AU - Bailey, Kent R.

AU - Boerwinkle, Eric

AU - Beitelshees, Amber L.

AU - Tanaka, Toshihiro

AU - Kubo, Michiaki

AU - Pepine, Carl J.

AU - Cooper-DeHoff, Rhonda M.

AU - Johnson, Julie A.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Background--The majority of hypertensive individuals require combination antihypertensive therapy to achieve adequate blood pressure (BP) control. This study aimed to identify genetic variants associated with uncontrolled BP on combination therapy with a thiazide diuretic and a β-blocker. Methods and Results--A genome-wide association study of uncontrolled BP on combination therapy was conducted among 314 white participants of the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) trial. Multivariable logistic regression analysis was used. Genetic variants meeting a suggestive level of significance (P < 1.0E-05) were tested for replication in an external cohort, INVEST (International Verapamil-SR Trandolapril study). We also examined genome-wide variant associations with systolic and diastolic BP response on combination therapy and tested for replication. We discovered a single nucleotide polymorphism, the rs261316 major allele, at chromosome 15 in the gene ALDH1A2 associated with an increased odds of having uncontrolled BP on combination therapy (odds ratio: 2.56, 95% confidence interval, 1.69-3.88, P=8.64E-06). This single nucleotide polymorphism replicated (odds ratio: 1.86, 95% confidence interval, 1.35-2.57, P=0.001) and approached genome-wide significance in the metaanalysis between discovery and replication cohorts (odds ratio: 2.16, 95% confidence interval, 1.63-2.86, P=8.60E-08). Other genes in the region surrounding rs261316 (ALDH1A2) include AQP9 and LIPC. Conclusions--A single nucleotide polymorphism in the gene ALDH1A2 may be associated with uncontrolled BP following treatment with a thiazide diuretic/β-blocker combination.

AB - Background--The majority of hypertensive individuals require combination antihypertensive therapy to achieve adequate blood pressure (BP) control. This study aimed to identify genetic variants associated with uncontrolled BP on combination therapy with a thiazide diuretic and a β-blocker. Methods and Results--A genome-wide association study of uncontrolled BP on combination therapy was conducted among 314 white participants of the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) trial. Multivariable logistic regression analysis was used. Genetic variants meeting a suggestive level of significance (P < 1.0E-05) were tested for replication in an external cohort, INVEST (International Verapamil-SR Trandolapril study). We also examined genome-wide variant associations with systolic and diastolic BP response on combination therapy and tested for replication. We discovered a single nucleotide polymorphism, the rs261316 major allele, at chromosome 15 in the gene ALDH1A2 associated with an increased odds of having uncontrolled BP on combination therapy (odds ratio: 2.56, 95% confidence interval, 1.69-3.88, P=8.64E-06). This single nucleotide polymorphism replicated (odds ratio: 1.86, 95% confidence interval, 1.35-2.57, P=0.001) and approached genome-wide significance in the metaanalysis between discovery and replication cohorts (odds ratio: 2.16, 95% confidence interval, 1.63-2.86, P=8.60E-08). Other genes in the region surrounding rs261316 (ALDH1A2) include AQP9 and LIPC. Conclusions--A single nucleotide polymorphism in the gene ALDH1A2 may be associated with uncontrolled BP following treatment with a thiazide diuretic/β-blocker combination.

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U2 - 10.1161/JAHA.117.006522

DO - 10.1161/JAHA.117.006522

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AN - SCOPUS:85034776600

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JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

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