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, 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

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 meta-analysis 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.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00246519.

Keywords: combination therapy; genomics; high blood pressure; hypertension; pharmacogenomics; thiazide diuretics; β‐blockers.

© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1
Figure 1
Association of rs261316 allele (T) in ALDH1A2 with uncontrolled BP on combination therapy in PEAR with replication analysis in INVEST. P values and 95% confidence intervals for INVEST cohorts are 1‐sided, consistent with a 1‐sided hypothesis for replication; sample sizes: PEAR whites (n=314), INVEST whites (n=221), and INVEST Hispanics (n=193). BP indicates blood pressure; INVEST, International Verapamil‐SR Trandolapril Study; PEAR, Pharmacogenomic Evaluation of Antihypertensive Responses.
Figure 2
Figure 2
Regional plot of top genetic variant associated with uncontrolled BP on combination therapy in PEAR with replication in INVEST. rs261316 associated with uncontrolled BP on combination therapy (PEAR whites: P=8.64E‐06; INVEST white–Hispanic meta‐analysis: 1‐sided P=0.001; PEAR and INVEST meta‐analysis: P=8.60E‐08); BP indicates blood pressure; INVEST, International Verapamil‐SR Trandolapril Study; PEAR, Pharmacogenomic Evaluation of Antihypertensive Responses.

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