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.
N1 - Funding Information:
Funding for PEAR comes from the National Institutes of Health (NIH) Pharmacogenetics Research Network grant U01 GM074492, the National Center for Advancing Translational Sciences under award numbers UL1 TR000064 (University of Florida), UL1 TR000454 (Emory University), and UL1 TR000135 (Mayo Clinic), the Mayo Foundation, and the National Heart Lung and Blood Institute grant R01 HL74730. INVEST was supported by the University of Florida and grants from BASF Pharma and Abbott Laboratories. Additional support for this project comes from NIH grants T32 DK104721 (Magvanjav) and KL2 TR001429 (McDonough).
Publisher Copyright:
© 2017 The Authors.
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
M3 - Article
C2 - 29097388
AN - SCOPUS:85034776600
VL - 6
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
SN - 2047-9980
IS - 11
M1 - e006522
ER -