Genome-Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β-Blockers.

Autor: Shahin MH; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL., Conrado DJ; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL., Gonzalez D; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina, Chapel Hill, NC., Gong Y; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL., Lobmeyer MT; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL., Beitelshees AL; Department of Medicine, University of Maryland, Baltimore, MD., Boerwinkle E; Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX., Gums JG; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL., Chapman A; Department of Medicine, The University of Chicago, IL., Turner ST; Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN., Cooper-DeHoff RM; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL., Johnson JA; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL johnson@cop.ufl.edu.
Jazyk: angličtina
Zdroj: Journal of the American Heart Association [J Am Heart Assoc] 2018 Feb 24; Vol. 7 (5). Date of Electronic Publication: 2018 Feb 24.
DOI: 10.1161/JAHA.117.006463
Abstrakt: Background: For many indications, the negative chronotropic effect of β-blockers is important to their efficacy, yet the heart rate (HR) response to β-blockers varies. Herein, we sought to use a genome-wide association approach to identify novel single nucleotide polymorphisms (SNPs) associated with HR response to β-blockers.
Methods and Results: We first performed 4 genome-wide association analyses for HR response to atenolol (a β1-adrenergic receptor blocker) as: (1) monotherapy or (2) add-on therapy, in 426 whites and 273 blacks separately from the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) study. A meta-analysis was then performed between the genome-wide association analysis performed in PEAR atenolol monotherapy and add-on therapy, in each race separately, using the inverse variance method assuming fixed effects. From this analysis, SNPs associated with HR response to atenolol at a P <1E-05 were tested for replication in whites (n=200) and blacks (n=168) treated with metoprolol (a β1-adrenergic receptor blocker). From the genome-wide association meta-analyses, SNP rs17117817 near olfactory receptor family10 subfamily-p-member1 ( OR10P1 ), and SNP rs2364349 in sorting nexin-9 ( SNX9 ) replicated in blacks. The combined studies meta-analysis P values for the rs17117817 and rs2364349 reached genome-wide significance (rs17117817G-allele; Meta-β=5.53 beats per minute, Meta- P =2E-09 and rs2364349 A-allele; Meta-β=3.5 beats per minute, Meta- P =1E-08). Additionally, SNPs in the OR10P1 and SNX9 gene regions were also associated with HR response in whites.
Conclusions: This study highlights OR10P1 and SNX9 as novel genes associated with changes in HR in response to β-blockers.
Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00246519.
(© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)
Databáze: MEDLINE
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