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β 2 ‐Adrenergic Receptor Gene Affects the Heart Rate Response of β‐Blockers: Evidence From 3 Clinical Studies
Author(s) -
Shahin Mohamed H.,
Rouby Nihal El,
Conrado Daniela J.,
Gonzalez Daniel,
Gong Yan,
Lobmeyer Maximilian T.,
Beitelshees Amber L.,
Boerwinkle Eric,
Gums John G.,
Chapman Arlene,
Turner Stephen T.,
Pepine Carl J.,
CooperDeHoff Rhonda M.,
Johnson Julie A.
Publication year - 2019
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1443
Subject(s) - metoprolol , atenolol , medicine , single nucleotide polymorphism , pear , carvedilol , meta analysis , heart rate , allele , genetic model , pharmacogenetics , pharmacology , endocrinology , cardiology , gene , genetics , blood pressure , biology , heart failure , genotype , botany
Abstract 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.