Ser49Gly of β-adrenergic receptor is associated with effective β-blocker dose in dilated cardiomyopathy

Objective Our objective was to evaluate the influence of polymorphisms at codons 49 and 389 of the β1-adrenergic receptor (β1-AR) on the response to β-blockers and outcome in patients with dilated cardiomyopathy. Methods We genotyped both codons of the β1-AR in 375 patients with dilated cardiomyopathy and 492 control subjects. Results Neither of the polymorphisms was associated with susceptibility for dilated cardiomyopathy. In a retrospective analysis of patients receiving β-blockers, there was a significant association between long-term survival rate and codon 49 (P = .014) but not codon 389 (P = .08). Despite a similar mean heart rate (69 beats/min), patients with the Ser49 genotype tended to have higher doses of β-blockade compared with Gly49 carriers (P = .065). In patients receiving a low dose of β-blockade (≤50% of targeted full dose), the 5-year mortality rate was lower among Gly49 carriers than Ser49 patients (risk ratio [RR], 0.24; 95% confidence interval [CI], 0.07–0.80; P = .020). In patients receiving high doses of β-blockers, there was no significant difference in outcome between genotypes (P = .20), which was attributable to a better outcome for Ser49 patients treated with a high dose of β-blockade as compared with a low dose. Gly49 carriers had a similar survival rate with different doses of β-blockers. With low-dose β-blockers, both codon 49 (RR, 0.26; 95% CI, 0.08–0.89; P = .029) and codon 389 (RR, 2.42; 95% CI, 1.04–5.63, P = .039) were related to 5-year mortality rate. Conclusion In patients with heart failure, the influence of codon 49 on the outcome and effect of β-blockers appeared to be more pronounced than that of codon 389. The more common Ser49Ser genotype responded less beneficially to β-blockade and would motivate genotyping to promote higher doses for the best outcome effect. Clinical Pharmacology & Therapeutics (2005) 78, 221–231; doi: 10.1016/j.clpt.2005.06.004