Article

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

Laboratory of Clinical Pharmacology Q7642, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
British Journal of Clinical Pharmacology (impact factor: 2.96). 04/2011; 71(4):556-65. DOI:10.1111/j.1365-2125.2010.03868.x
Source: PubMed

ABSTRACT 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 β(1) -receptor gene (ADRB1) and the Gln27Glu polymorphism in the adrenergic β(2) -receptor gene (ADRB2) could predict survival in carvedilol- and metoprolol-treated chronic heart failure (HF) patients.
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.
There was a significant interaction between functional genotype group and carvedilol treatment (adjusted(1) P= 0.033, adjusted(2) P= 0.040). Patients treated with carvedilol had shorter survival in functional genotype group 1 (P= 0.004; adjusted(1) hazard ratio (HR) 2.67, 95% CI 1.27, 5.59, P= 0.010; adjusted(2) 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).
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.

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Keywords

ADRB2 Gln27-carrier
 
ADRB2 Gln27Glu
 
cardiovascular medicine
 
carvedilol treatment
 
functional genotype group
 
functional genotype group 1
 
functional genotype groups
 
genotype combination
 
genotype group
 
genotype group 1
 
genotype groups
 
group 1 combination
 
median follow-up time
 
metoprolol treatment
 
metoprolol-treated chronic heart failure
 
metoprolol-treated HF patients
 
multivariate Cox models
 
predefined combination
 
significant interaction
 
stratified pharmacological therapy