1. 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.
- Author
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Magvanjav O, Gong Y, McDonough CW, Chapman AB, Turner ST, Gums JG, Bailey KR, Boerwinkle E, Beitelshees AL, Tanaka T, Kubo M, Pepine CJ, Cooper-DeHoff RM, and Johnson JA
- Subjects
- Adolescent, Adrenergic beta-Antagonists adverse effects, Adult, Aged, Aldehyde Dehydrogenase 1 Family, Angiotensin-Converting Enzyme Inhibitors therapeutic use, Antihypertensive Agents adverse effects, Atenolol adverse effects, Calcium Channel Blockers therapeutic use, Chi-Square Distribution, Drug Combinations, Female, Florida, Genome-Wide Association Study, Georgia, Humans, Hydrochlorothiazide adverse effects, Hypertension diagnosis, Hypertension physiopathology, Indoles therapeutic use, Logistic Models, Male, Middle Aged, Multivariate Analysis, Odds Ratio, Pharmacogenetics, Prospective Studies, Risk Factors, Sodium Chloride Symporter Inhibitors adverse effects, Treatment Outcome, Vasodilator Agents therapeutic use, Verapamil therapeutic use, Young Adult, Adrenergic beta-Antagonists therapeutic use, Antihypertensive Agents therapeutic use, Atenolol therapeutic use, Blood Pressure drug effects, Drug Resistance genetics, Hydrochlorothiazide therapeutic use, Hypertension drug therapy, Hypertension genetics, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Retinal Dehydrogenase genetics, Sodium Chloride Symporter Inhibitors therapeutic use
- 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., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)
- Published
- 2017
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