β 2 -Adrenergic Receptor Gene Affects the Heart Rate Response of β-Blockers: Evidence From 3 Clinical Studies

Mohamed H. Shahin, Nihal El Rouby, Daniela J. Conrado, Daniel Gonzalez, Yan Gong, Maximilian T. Lobmeyer, Amber L. Beitelshees, Eric Boerwinkle, John G. Gums, Arlene Chapman, Stephen T Turner, Carl J. Pepine, Rhonda M. Cooper-DeHoff, Julie A. Johnson

Research output: Contribution to journalArticle

Abstract

β-Blockers’ heart rate (HR)-lowering effect is an important determinant of the effectiveness for this class of drugs, yet it is variable among β-blocker–treated patients. To date, genetic studies have revealed several genetic signals associated with HR response to β-blockers. However, these genetic signals have not been consistently replicated across multiple independent cohorts. Here we sought to use data from 3 hypertension clinical trials to validate single-nucleotide polymorphisms (SNPs) previously associated with the HR response to β-blockers. Using linear regression analysis, we investigated the effects of 6 SNPs in 3 genes, including ADRB1, ADRB2, and GNB3, relative to the HR response following β-blocker used in the PEAR (n = 757), PEAR-2 (n = 368), and INVEST (n = 1401) trials, adjusting for baseline HR, age, sex, and ancestry. Atenolol was used in PEAR and INVEST, and metoprolol was used in PEAR-2. We found that rs1042714 and rs1042713 in ADRB2 were significantly associated with HR response to both β-blockers in whites (rs1042714 C-allele carriers, meta-analysis β = –0.95 beats per minute [bpm], meta-analysis P = 3×10 –4 ; rs1042713 A-allele carriers, meta-analysis β = –1.15 bpm, meta-analysis P = 2×10 –3 ). In conclusion, the results of our analyses provide strong evidence to support the hypothesis that rs1042714 and rs1042713 in the ADRB2 gene are important predictors of HR response to cardioselective β-blockade in hypertensive patient cohorts.

Original languageEnglish (US)
JournalJournal of Clinical Pharmacology
DOIs
StatePublished - Jan 1 2019

Fingerprint

Adrenergic Receptors
Heart Rate
Meta-Analysis
Genes
Single Nucleotide Polymorphism
Alleles
Metoprolol
Atenolol
Clinical Studies
Linear Models
Regression Analysis
Clinical Trials
Hypertension
Pharmaceutical Preparations

Keywords

  • atenolol
  • heart rate
  • metoprolol
  • Pharmacogenetics
  • β-blockers

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

β 2 -Adrenergic Receptor Gene Affects the Heart Rate Response of β-Blockers : Evidence From 3 Clinical Studies. / Shahin, Mohamed H.; Rouby, Nihal El; Conrado, Daniela J.; Gonzalez, Daniel; Gong, Yan; Lobmeyer, Maximilian T.; Beitelshees, Amber L.; Boerwinkle, Eric; Gums, John G.; Chapman, Arlene; Turner, Stephen T; Pepine, Carl J.; Cooper-DeHoff, Rhonda M.; Johnson, Julie A.

In: Journal of Clinical Pharmacology, 01.01.2019.

Research output: Contribution to journalArticle

Shahin, MH, Rouby, NE, Conrado, DJ, Gonzalez, D, Gong, Y, Lobmeyer, MT, Beitelshees, AL, Boerwinkle, E, Gums, JG, Chapman, A, Turner, ST, Pepine, CJ, Cooper-DeHoff, RM & Johnson, JA 2019, 'β 2 -Adrenergic Receptor Gene Affects the Heart Rate Response of β-Blockers: Evidence From 3 Clinical Studies', Journal of Clinical Pharmacology. https://doi.org/10.1002/jcph.1443
Shahin, Mohamed H. ; Rouby, Nihal El ; Conrado, Daniela J. ; Gonzalez, Daniel ; Gong, Yan ; Lobmeyer, Maximilian T. ; Beitelshees, Amber L. ; Boerwinkle, Eric ; Gums, John G. ; Chapman, Arlene ; Turner, Stephen T ; Pepine, Carl J. ; Cooper-DeHoff, Rhonda M. ; Johnson, Julie A. / β 2 -Adrenergic Receptor Gene Affects the Heart Rate Response of β-Blockers : Evidence From 3 Clinical Studies. In: Journal of Clinical Pharmacology. 2019.
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AU - Conrado, Daniela J.

AU - Gonzalez, Daniel

AU - Gong, Yan

AU - Lobmeyer, Maximilian T.

AU - Beitelshees, Amber L.

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AU - Gums, John G.

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