TY - JOUR

T1 - Association of beta-adrenergic receptor polymorphisms and mortality in carvedilol-treated chronic heart-failure patients

AU - Petersen, Morten

AU - Andersen, Jon T

AU - Hjelvang, Brian R

AU - Broedbaek, Kasper

AU - Afzal, Shoaib

AU - Nyegaard, Mette

AU - Børglum, Anders

AU - Stender, Steen

AU - Køber, Lars

AU - Torp-Pedersen, Christian

AU - Poulsen, Henrik E

N1 - © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

PY - 2011/4/1

Y1 - 2011/4/1

N2 - 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 ß-adrenoceptor blockers for its treatment has improved survival considerably. • As is the case for all medical treatment, not all patients benefit from ß-adrenoceptor blocker treatment, and stratifying patients to different ß-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 ß-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 ß(1) -receptor gene (ADRB1) and the Gln27Glu polymorphism in the adrenergic ß(2) -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 (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). 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.

AB - 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 ß-adrenoceptor blockers for its treatment has improved survival considerably. • As is the case for all medical treatment, not all patients benefit from ß-adrenoceptor blocker treatment, and stratifying patients to different ß-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 ß-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 ß(1) -receptor gene (ADRB1) and the Gln27Glu polymorphism in the adrenergic ß(2) -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 (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). 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.

U2 - 10.1111/j.1365-2125.2010.03868.x

DO - 10.1111/j.1365-2125.2010.03868.x

M3 - Journal article

C2 - 21395649

VL - 71

SP - 556

EP - 565

JO - British Journal of Clinical Pharmacology, Supplement

JF - British Journal of Clinical Pharmacology, Supplement

SN - 0264-3774

IS - 4

ER -