beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension

• Published in: Clinical pharmacology and therapeutics Vol. 84; no. 6; p. 715
• Main Authors: Pacanowski, M A, Gong, Y, Cooper-Dehoff, R M, Schork, N J, Shriver, M D, Langaee, T Y, Pepine, C J, Johnson, J A
• Format: Journal Article
• Language: English
• Published: United States 01.12.2008
• Subjects: Adrenergic beta-Antagonists - administration & dosage; Aged; Atenolol - administration & dosage; Atenolol - pharmacokinetics; Confidence Intervals; Coronary Disease - drug therapy; Coronary Disease - genetics; Coronary Disease - mortality; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Heterozygote; Humans; Hypertension - drug therapy; Hypertension - genetics; Hypertension - mortality; Male; Middle Aged; Pharmacogenetics; Polymorphism, Genetic; Probability; Proportional Hazards Models; Receptors, Adrenergic, beta-1 - drug effects; Receptors, Adrenergic, beta-1 - genetics; Receptors, Adrenergic, beta-2 - drug effects; Receptors, Adrenergic, beta-2 - genetics; Reference Values; Risk Assessment; Survival Analysis; Treatment Outcome; Verapamil - administration & dosage; Verapamil - pharmacokinetics
• ISSN: 1532-6535
• DOI: 10.1038/clpt.2008.139

Numerous studies have demonstrated that beta(1)- and beta(2)-adrenergic receptor gene (ADRB1 and ADRB2) variants influence cardiovascular risk and beta-blocker responses in hypertension and heart failure. We evaluated the relationship between ADRB1 and ADRB2 haplotypes, cardiovascular risk (death, nonfatal myocardial infarction (MI), and nonfatal stroke), and atenolol-based vs. verapamil sustained-release (SR)-based antihypertensive therapy in 5,895 coronary artery disease (CAD) patients. After an average of 2.8 years, death rates were higher in patients carrying the ADRB1 Ser49-Arg389 haplotype (hazard ratio (HR) 3.66, 95% confidence interval (95% CI) 1.68-7.99). This mortality risk was significant in patients randomly assigned to verapamil SR (HR 8.58, 95% CI 2.06-35.8) but not atenolol (HR 2.31, 95% CI 0.82-6.55), suggesting a protective role for the beta-blocker. ADRB2 haplotype associations were divergent within the treatment groups but did not remain significant after adjustment for multiple comparisons. ADRB1 haplotype variation is associated with mortality risk, and beta-blockers may be preferred in subgroups of patients defined by ADRB1 or ADRB2 polymorphisms.