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

Publication ,  Journal Article
Shahin, MH; Conrado, DJ; Gonzalez, D; Gong, Y; Lobmeyer, MT; Beitelshees, AL; Boerwinkle, E; Gums, JG; Chapman, A; Turner, ST; Johnson, JA ...
Published in: J Am Heart Assoc
February 24, 2018

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.

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Published In

J Am Heart Assoc

DOI

EISSN

2047-9980

Publication Date

February 24, 2018

Volume

7

Issue

5

Location

England

Related Subject Headings

  • White People
  • Sorting Nexins
  • Receptors, Odorant
  • Randomized Controlled Trials as Topic
  • Polymorphism, Single Nucleotide
  • Phenotype
  • Pharmacogenomic Variants
  • Pharmacogenetics
  • Middle Aged
  • Male
 

Citation

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Shahin, M. H., Conrado, D. J., Gonzalez, D., Gong, Y., Lobmeyer, M. T., Beitelshees, A. L., … Johnson, J. A. (2018). Genome-Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β-Blockers. J Am Heart Assoc, 7(5). https://doi.org/10.1161/JAHA.117.006463
Shahin, Mohamed H., Daniela J. Conrado, Daniel Gonzalez, Yan Gong, Maximilian T. Lobmeyer, Amber L. Beitelshees, Eric Boerwinkle, et al. “Genome-Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β-Blockers.J Am Heart Assoc 7, no. 5 (February 24, 2018). https://doi.org/10.1161/JAHA.117.006463.
Shahin MH, Conrado DJ, Gonzalez D, Gong Y, Lobmeyer MT, Beitelshees AL, et al. Genome-Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β-Blockers. J Am Heart Assoc. 2018 Feb 24;7(5).
Shahin, Mohamed H., et al. “Genome-Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β-Blockers.J Am Heart Assoc, vol. 7, no. 5, Feb. 2018. Pubmed, doi:10.1161/JAHA.117.006463.
Shahin MH, Conrado DJ, Gonzalez D, Gong Y, Lobmeyer MT, Beitelshees AL, Boerwinkle E, Gums JG, Chapman A, Turner ST, Cooper-DeHoff RM, Johnson JA. Genome-Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β-Blockers. J Am Heart Assoc. 2018 Feb 24;7(5).
Journal cover image

Published In

J Am Heart Assoc

DOI

EISSN

2047-9980

Publication Date

February 24, 2018

Volume

7

Issue

5

Location

England

Related Subject Headings

  • White People
  • Sorting Nexins
  • Receptors, Odorant
  • Randomized Controlled Trials as Topic
  • Polymorphism, Single Nucleotide
  • Phenotype
  • Pharmacogenomic Variants
  • Pharmacogenetics
  • Middle Aged
  • Male