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

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

Abstract

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.

Keywords: atenolol; heart rate; metoprolol; pharmacogenomics; β‐blockers.

© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1
Figure 1
PEAR study design. ATEN indicates atenolol; HCTZ, hydrochlorothiazide; HR, heart rate; PEAR, Pharmacogenomics Evaluation of Antihypertensive Response.
Figure 2
Figure 2
The overall analysis framework of the study. GWAS indicates genome‐wide association study; PEAR, Pharmacogenomics Evaluation of Antihypertensive Response; SNP, single nucleotide polymorphism.
Figure 3
Figure 3
Effect of rs17117817 and rs2364349 polymorphisms on the β‐blocker HR response in whites within PEAR and PEAR‐2 studies. A, rs17117817. B, rs2364349. The box represents the values from the 25% to 75% percentile. The horizontal line represents the median. The black diamond represents the mean. The vertical line extends from the minimum to the maximum value. Each blue dot represents an individual. HR response was adjusted for age, sex, baseline HR, differences in dose, and principal components 1 and 2. Two‐sided P values represented are for the contrast of adjusted means between different genotype groups. *Meta‐analysis was performed assuming fixed effects and using inverse‐variance weighting. bpm indicates beats per minute; HR, heart rate; OR10P1, olfactory receptor family 10 subfamily p member 1; PEAR, Pharmacogenomic Evaluation of Antihypertensive Responses; SNX9, sorting nexin 9.
Figure 4
Figure 4
Regional plot showing the significance of the associations of SNPs with changes in HR in response to β‐blockers used in whites. A, In olfactory receptor family 10 subfamily p member 1 (OR10P1) genetic region. B, In sorting nexin‐9 (SNX9) genetic region. HR indicates heart rate; SNP, single nucleotide polymorphism.
Figure 5
Figure 5
β‐Blocker's HR response score in PEAR and PEAR‐2. HR responses were adjusted for age, sex, baseline HR, differences in dose, and principal components 1 and 2. Genetic variants were coded as follows: (A) rs17117817 (OR10P1 genetic region) T/T=2, G/T=1, G/G=zero, and (B) rs2364349 (SNX9 genetic region) G/G=2, A/G=1, A/A=zero. The box represents the values from the 25% to 75% percentile. The horizontal line represents the median. The vertical line extends from the minimum to the maximum value. Each blue dot represents an individual. bpm indicates beats per minute HR, heart rate; PEAR, Pharmacogenomic Evaluation of Antihypertensive Responses. *Meta‐analysis was performed between PEAR atenolol monotherapy, PEAR atenolol add‐on therapy, and PEAR‐2 metoprolol groups, assuming fixed effects and using inverse‐variance weighting.
Figure 6
Figure 6
Interaction network of replicated genetic signals and protein targets for β‐blockers. Network was created using the STRING database (https://string-db.org/).

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