title: Effect of specific ADRB1/ADRB2/AGT genotype combinations on the association between survival and carvedilol treatment in chronic heart failure:  a substudy of the ECHOS trial.
abstract: OBJECTIVE
  The aim of the present study was to determine whether carvedilol-treated chronic heart failure patients have a different prognosis when stratified for a specific combination of a gain-of-function genotype of the adrenergic β-1 receptor gene (ADRB1) (Arg389-homozygous), two gain-of-function genotypes of the angiotensinogen gene (AGT) (Thr174-homozygous and Thr235-homozygous), and a downregulated genotype of the adrenergic β-2 receptor gene (ADRB2) (Gln27-carrier).
  
  
  METHODS
  Genotyping of 618 patients was carried out using the Sequenoms MassARRAY genotyping system. Outcome was all-cause mortality and statistics were calculated using a multivariable Cox proportional hazards model. Internal validation was performed using the bootstrap procedure.
  
  
  RESULTS
  Eighty-seven of the 618 patients included in the study were treated with carvedilol. There was a significant interaction between the outcome of carvedilol treatment and the combination of the gain-of-function ADRB1 genotype (Arg389-homozygous) and the gain-of-function AGT genotype (Thr174-homozygous) (P(interaction)=0.003; hazard ratio 2.19, 95% confidence interval 1.26-3.78, P=0.005). There was also a significant interaction when the downregulated ADRB2 genotype (Gln27-carrier) was added to the ADRB1/AGT combination (P(interaction)=0.0005; hazard ratio 2.67, 95% confidence interval 1.51-4.72, P=0.0007). Two hundred and four patients were treated with metoprolol. There was no interaction between metoprolol treatment and the specific genotype combinations as there was no difference in the overall survival. The validity of the results was supported by the bootstrap procedure.
  
  
  CONCLUSIONS
  We found a doubling of the hazard of mortality in carvedilol-treated patients with the combination of the gain-of-function ADRB1 genotype (Arg389-homozygous), the gain-of-function AGT genotype (Thr174-homozygous), and the downregulated ADRB2 genotype (Gln27-carrier). This might be valuable when stratifying chronic heart failure patients to the right β-blocker therapy.
authors: Laboratory of Clinical Pharmacology Q7642, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. mortenpetersen@rh.dk
authors: Morten
authors: M
authors: Petersen
authors: Jon T
authors: JT
authors: Andersen
authors: Espen
authors: E
authors: Jimenez-Solem
authors: Kasper
authors: K
authors: Broedbaek
authors: Shoaib
authors: S
authors: Afzal
authors: Mette
authors: M
authors: Nyegaard
authors: Anders D
authors: AD
authors: Børglum
authors: Steen
authors: S
authors: Stender
authors: Christian
authors: C
authors: Torp-Pedersen
authors: Lars
authors: L
authors: Køber
authors: Henrik E
authors: HE
authors: Poulsen
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000808:Angiotensinogen / Q000235:genetics*; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D002908:Chronic Disease; D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011412:Propanolamines / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012189:Retrospective Studies; D016019:Survival Analysis
chemical_list: C547787:ADRB1 protein, human; C553443:ADRB2 protein, human; C534931:AGT protein, human; D058668:Adrenergic alpha-1 Receptor Antagonists; D002227:Carbazoles; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D000077261:Carvedilol; D000808:Angiotensinogen