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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00133692.

Conflict of interest statement

Conflict of interest

Drs Johnson, Pepine, Cooper-DeHoff, and Langaee received grant funding from Abbott Laboratories. Drs Cooper-DeHoff and Pepine along with the University of Florida hold U.S. patent 5,991,731 related to INVEST. Dr Pepine has been a consultant for Abbott Laboratories. The other authors declared no conflict of interest.

Figures

Figure 1

Associations of the ADRB1 Ser49-Arg389 haplotype with primary and secondary outcomes. Hazard ratios are based on reduced model adjusted for age, sex, and race/ethnicity. *Crude incidence per 1,000 patient years. MI, myocardial infarction.

Figure 2

All-cause mortality and mean on-treatment blood pressure by ADRB1 Ser49-Arg389 haplotype and atenolol/verapamil sustained-release (SR) therapy. HR, hazard ratio; 95% CI, 95% confidence interval; S49-R389, Ser49-Arg389 haplotype; AT, atenolol; VE, verapamil SR; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Figure 3

Primary and secondary outcomes by ADRB2 Gly16-Glu27-523C haplotype and antihypertensive drug therapy. *Crude incidence per 1,000 patient years. †Includes only patients ever exposed to atenolol (94% in atenolol strategy). ‡Hazard ratios based on reduced model adjusted for age, sex, and race/ ethnicity. MI, myocardial infarction; SR, sustained release.