title: Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in beta-blocker users.
abstract: Several beta-blockers are metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). CYP2D6*4 is the main polymorphism leading to decreased enzyme activity. The clinical significance of impaired elimination of beta-blockers is controversial, and most studies suffer from inclusion of small numbers of poor metabolizers (PMs) of CYP2D6. In this study, the association between CYP2D6*4 and blood pressure or heart rate was examined in 1,533 users of beta-blockers in the Rotterdam Study, a population-based cohort study. In CYP2D6 *4/*4 PMs, the adjusted heart rate in metoprolol users was 8.5 beats/min lower compared with *1/*1 extensive metabolizers (EMs) (P < 0.001), leading to an increased risk of bradycardia in PMs (odds ratio = 3.86; 95% confidence interval 1.68-8.86; P = 0.0014). The diastolic blood pressure in PMs was 5.4 mm Hg lower in users of beta-blockers metabolized by CYP2D6 (P = 0.017) and 4.8 mm Hg lower in metoprolol users (P = 0.045) compared with EMs. PMs are at increased risk of bradycardia.
authors.affiliation: Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Bijl
authors.forename: L E
authors.initials: LE
authors.lastname: Visser
authors.forename: R H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: J A
authors.initials: JA
authors.lastname: Kors
authors.forename: J C M
authors.initials: JC
authors.lastname: Witteman
authors.forename: A
authors.initials: A
authors.lastname: Hofman
authors.forename: A G
authors.initials: AG
authors.lastname: Vulto
authors.forename: T
authors.initials: T
authors.lastname: van Gelder
authors.forename: B H Ch
authors.initials: BH
authors.lastname: Stricker
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects*; D003430:Cross-Sectional Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005828:Genetics, Population / Q000379:methods*; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D008790:Metoprolol / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D009426:Netherlands; D011110:Polymorphism, Genetic
chemical_list: D000319:Adrenergic beta-Antagonists; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol