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

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: https://www.clinicaltrials.gov. Unique identifier: NCT00246519.