Association of beta‐adrenergic receptor polymorphisms and mortality in carvedilol‐treated chronic heart‐failure patients

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Chronic heart failure (HF) is a syndrome with increasing prevalence. Though mortality is still high, the introduction of β‐adrenoceptor blockers for its treatment has improved survival considerably. • As is the case for all medical treatment, not all patients benefit from β‐adrenoceptor blocker treatment, and stratifying patients to different β‐adrenoceptor blockers by the use of pharmacogenomics might be of great value in improving HF therapy. • Previous studies have shown that the two single nucleotide polymorphisms (SNPs) ADRB1 Arg389Gly and ADRB2 Gln27Glu interact with the β‐adrenoceptor blockers metoprolol and carvedilol, respectively. These interactions have led to stratified responses with regard to surrogate parameters, e.g. left ventricular ejection fraction (LVEF), pulse and blood pressure. • Several studies have failed to show a stratified survival response when stratifying for ADRB1 Arg389Gly and ADRB2 Gln27Glu. WHAT THIS STUDY ADDS • With the present study we tested a specific combination of ADRB1 Arg389Gly and ADRB2 Gln27Glu and showed that, when stratifying HF patients according to this genotype combination, a stratified carvedilol response was seen with respect to survival over a median follow‐up period of 6.7 years. • This genotype combination did not show a stratified metoprolol response. AIM Pharmacogenetics can be used as a tool for stratified pharmacological therapy in cardiovascular medicine. We investigated whether a predefined combination of the Arg389Gly polymorphism in the adrenergic β₁‐receptor gene (ADRB1) and the Gln27Glu polymorphism in the adrenergic β₂‐receptor gene (ADRB2) could predict survival in carvedilol‐ and metoprolol‐treated chronic heart failure (HF) patients. METHODS Five hundred and eighty‐six HF patients (carvedilol n= 82, metoprolol n= 195) were genotyped for ADRB1 Arg389Gly (rs1801253) and ADRB2 Gln27Glu (rs1042714). The end‐point was all‐cause mortality, and median follow‐up time was 6.7 years. Patients were classified into two functional genotype groups: group 1 combination of Arg389‐homozygous and Gln27‐carrier (46%) and group 2 any other genotype combination (54%). Results were fitted in two multivariate Cox models. RESULTS There was a significant interaction between functional genotype group and carvedilol treatment (adjusted₁P= 0.033, adjusted₂P= 0.040). Patients treated with carvedilol had shorter survival in functional genotype group 1 (P= 0.004; adjusted₁ hazard ratio (HR) 2.67, 95% CI 1.27, 5.59, P= 0.010; adjusted₂ HR 2.05, 95% CI 1.06, 3.95, P= 0.033). There was no interaction between genotype group and metoprolol treatment (P= 0.61), and there was no difference in overall survival between genotype groups (P= 0.69). CONCLUSIONS A combination of ADRB1 Arg389‐homozygous and ADRB2 Gln27‐carrier in HF patients treated with carvedilol was associated with a two‐fold increase in mortality relative to all other genotype combinations. There was no difference in survival in metoprolol‐treated HF patients between genotype groups. Patients in genotype group 1 may benefit more from metoprolol than carvedilol treatment.