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 - Funding Information:
PEAR and PEAR-2 were supported by the National Institutes of Health Pharmacogenetics Research Network grant U01 GM074492 and the National Center for Advancing Translational Sciences under the award numbers UL1 TR000064 (University of Florida), UL1 TR000454 (Emory University), and UL1 TR000135 (Mayo Clinic). Funds from the Mayo Foundation also supported the PEAR study. INVEST was supported by grants from the University of Florida Opportunity Fund and Abbott Pharmaceuticals. INVEST-GENES was supported by National Institutes of Health grants (U01 GM074492 and R01 HL074730). D.G. receives support for research from the National Institute of Child Health and Human Development (K23HD083465). We thank the study participants enrolled in the PEAR, PEAR-2, and INVEST studies. We also acknowledge the valuable support of the staff and study physicians in each of these studies. PEAR and PEAR-2 genomics and phenotype data are publicly available at the database of Genotypes and Phenotypes (dbGaP; https://www.ncbi.nlm.nih.gov/gap) PEAR and PEAR-2 were supported by the National Institutes of Health Pharmacogenetics Research Network grant U01 GM074492 and the National Center for Advancing Translational Sciences under the award numbers UL1 TR000064 (University of Florida), UL1 TR000454 (Emory University), and UL1 TR000135 (Mayo Clinic). Funds from the Mayo Foundation also supported the PEAR study. INVEST was supported by grants from the University of Florida Opportunity Fund and Abbott Pharmaceuticals. INVEST-GENES was supported by National Institutes of Health grants (U01 GM074492 and R01 HL074730). D.G. receives support for research from the National Institute of Child Health and Human Development (K23HD083465). None
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
VL - 59
SP - 1462
EP - 1470
JO - Journal of Clinical Pharmacology
JF - Journal of Clinical Pharmacology
SN - 0091-2700
IS - 11
ER -