TY - JOUR
T1 - β2-Adrenergic Receptor Gene Affects the Heart Rate Response of β-Blockers
T2 - Evidence From 3 Clinical Studies
AU - Shahin, Mohamed H.
AU - Rouby, Nihal El
AU - Conrado, Daniela J.
AU - Gonzalez, Daniel
AU - Gong, Yan
AU - Lobmeyer, Maximilian T.
AU - Beitelshees, Amber L.
AU - Boerwinkle, Eric
AU - Gums, John G.
AU - Chapman, Arlene
AU - Turner, Stephen T.
AU - Pepine, Carl J.
AU - Cooper-DeHoff, Rhonda M.
AU - Johnson, Julie A.
N1 - Publisher Copyright:
© 2019, The American College of Clinical Pharmacology
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
KW - Pharmacogenetics
KW - atenolol
KW - heart rate
KW - metoprolol
KW - β-blockers
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U2 - 10.1002/jcph.1443
DO - 10.1002/jcph.1443
M3 - Article
C2 - 31090079
AN - SCOPUS:85065920866
SN - 0091-2700
VL - 59
SP - 1462
EP - 1470
JO - Journal of Clinical Pharmacology
JF - Journal of Clinical Pharmacology
IS - 11
ER -