Conrado, Daniela J.

Abstractβ‐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.

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 ( SNP s) 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, SNP s 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 ( OR 10P1 ), and SNP rs2364349 in sorting nexin‐9 ( SNX 9 ) 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, SNP s in the OR 10P1 and SNX 9 gene regions were also associated with HR response in whites. Conclusions This study highlights OR 10P1 and SNX 9 as novel genes associated with changes in HR in response to β‐blockers. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00246519.