title: Relation of ADRB1, CYP2D6, and UGT1A1 polymorphisms with dose of, and response to, carvedilol or metoprolol therapy in patients with chronic heart failure.
abstract: The response to beta blockers in patients with heart failure could be associated with the genotype of drug-metabolizing enzymes and/or drug targets. The purpose of the present study was to determine whether specific genetic polymorphisms in ADRB1 (encoding the beta1-adrenergic receptor), CYP2D6, and UGT1A1 correlated with dose of, or response to, metoprolol or carvedilol treatment in patients with heart failure. A cohort of patients with heart failure (n = 93), characterized as responders or nonresponders to metoprolol (n = 19) or carvedilol (n = 74) therapy, was retrospectively identified. Individual genotyping was performed for a panel of polymorphisms in the ADRB1, CYP2D6, and UGT1A1 genes. Univariate and multivariate analyses were performed to compare the genotype to the metoprolol or carvedilol response status and dose. A nonresponse was identified in 10 of 19 patients taking metoprolol and 32 of 74 patients taking carvedilol. None of the polymorphisms in ADRB1, CYP2D6, and UGT1A1 were associated with a response or nonresponse. However, a significant relation between the carvedilol (but not metoprolol) dose and the ADRB1 and CYP2D6 genotype was observed. Patients homozygous for the ADRB1 389Gly variant or who were CYP2D6 poor metabolizers achieved a significantly higher dose of carvedilol (p = 0.01 and p = 0.02, respectively). In conclusion, polymorphisms in ADRB1, CYP2D6, and UGT1A1 were not associated with a response to metoprolol or carvedilol therapy in our cohort of patients with heart failure. The ADRB1 and CYP2D6 genotype, alone and in haplotype, were significantly associated with the dose of carvedilol.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA. baudhuin.linnea@mayo.edu
authors.forename: Linnea M
authors.initials: LM
authors.lastname: Baudhuin
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Miller
authors.forename: Laura
authors.initials: L
authors.lastname: Train
authors.forename: Sandra
authors.initials: S
authors.lastname: Bryant
authors.forename: Karen A
authors.initials: KA
authors.lastname: Hartman
authors.forename: Mary
authors.initials: M
authors.lastname: Phelps
authors.forename: Mary
authors.initials: M
authors.lastname: Larock
authors.forename: Allan S
authors.initials: AS
authors.lastname: Jaffe
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000368:Aged; D000483:Alleles; D002227:Carbazoles / Q000008:administration & dosage*; D000077261:Carvedilol; D002908:Chronic Disease; D015897:Comorbidity; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics* / Q000628:therapy; D006801:Humans; D016014:Linear Models; D008790:Metoprolol / Q000008:administration & dosage*; D008875:Middle Aged; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011412:Propanolamines / Q000008:administration & dosage*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D000077261:Carvedilol; D019389:Cytochrome P-450 CYP2D6; D014453:Glucuronosyltransferase; D008790:Metoprolol; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D000099148:UGT1A1 Enzyme; C547787:ADRB1 protein, human