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