Beta2-adrenergic receptor genotype and survival among patients receiving beta-blocker therapy after an acute coronary syndrome

Abstract

Context: Previous data support an association between polymorphisms of the beta1- and beta2-adrenergic receptors (ADRB1 and ADRB2) and surrogate end points of response to beta-adrenergic blocker therapy. However, no associations between these polymorphisms and mortality have been demonstrated.

Objective: To evaluate the effect of ADRB1 Arg389Gly (1165 CG), Ser49Gly (145 AG), and ADRB2 Gly16Arg (46 GA), Gln27Glu (79 CG) genotypes on survival among patients discharged with prescribed beta-blockers after an acute coronary syndrome (ACS).

Design, setting, and patients: Prospective cohort study of 735 ACS patients admitted to 2 Kansas City, Mo, medical centers between March 2001 and October 2002; 597 patients were discharged with beta-blocker therapy.

Main outcome measure: Multivariable-adjusted time to all-cause 3-year mortality.

Results: There were 84 deaths during follow-up. There was a significant association between ADRB2 genotype and 3-year mortality among patients prescribed beta-blocker therapy. For the 79 CG polymorphism, Kaplan-Meier 3-year mortality rates were 16% (35 deaths), 11% (27 deaths), and 6% (4 deaths) for the CC, CG, and GG genotypes, respectively (P = .03; adjusted hazard ratios [AHRs], 0.51 [95% confidence interval {CI}, 0.30-0.87] for CG vs CC and 0.24 (95% CI, 0.09-0.68) for GG vs CC, P = .004). For the ADRB2 46 GA polymorphism, 3-year Kaplan-Meier mortality estimates were 10% (17 deaths), 10% (28 deaths), and 20% (20 deaths) for the GG, GA, and AA genotypes, respectively (P = .005; AHRs, 0.48 [95% CI, 0.27-0.86] for GA vs AA and 0.44 [95% CI, 0.22-0.85] for GG vs AA, P = .02). No mortality difference between genotypes was found among patients not discharged with beta-blocker therapy for either the 79 CG or 46 GA polymorphisms (P = .98 and P = .49, respectively). The ADRB2 diplotype and compound genotypes were predictive of survival in patients treated with beta-blockers (P = .04 and P = .002; AHRs, 5.36 [95% CI, 1.83-15.69] and 2.41 [95% CI, 0.86-6.74] for 46 A homozygous and composite heterozygous vs 79 G homozygous, respectively). No association of the ADRB1 variants with mortality was observed in either the beta-blocker or no beta-blocker groups.

Conclusions: Patients prescribed beta-blocker therapy after an ACS have differential survival associated with their ADRB2 genotypes. Further assessment of the benefits of beta-blocker therapy in high-risk genotype groups may be warranted.