title: ABCB1 gene variants, digoxin and risk of sudden cardiac death in a general population.
abstract: OBJECTIVE
  The ATP-binding cassette B1 (ABCB1) gene encodes P-glycoprotein, a transport protein, which plays an important role in the bioavailability of digoxin. We aimed to investigate the interaction between variants within the ABCB1 gene and digoxin on the risk of sudden cardiac death (SCD).
  
  
  METHODS
  Within the Rotterdam Study, a population-based cohort study in persons 45 years of age and older, we used Cox regression to analyse the association between three polymorphisms that have been associated with digoxin bioavailability, extracted from 1000-Genomes imputed ABCB1 genotypes and the risk of SCD, stratified by digoxin use.
  
  
  RESULTS
  In a total study population of 10,932 persons, 419 SCDs occurred during a median follow-up of 9.8 years. In non-users of digoxin, the risk of SCD was not different across genotypes. In digoxin users, homozygous T allele carriers of C1236T (HR 1.90; 95% CI 1.09 to 3.30; allele frequency 0.43), G2677T (HR 1.89; 95% CI 1.10 to 3.24; allele frequency 0.44) and C3435T (HR 1.72; 95% CI 1.03 to 2.87; allele frequency 0.53) had a significantly increased risk of SCD in a recessive model. Interaction between the ABCB1 polymorphisms and digoxin use was significant for C1236T and G2677T in the age-adjusted and sex-adjusted model.
  
  
  CONCLUSIONS
  In this study, we showed that in digoxin users variant alleles at each of the three loci in the ABCB1 gene were associated with an increased risk of SCD compared with digoxin users with none or one T allele. If replicated, the findings imply that the ABCB1 genotype modifies the risk of cardiac digoxin toxicity.
authors.affiliation: Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Maartje N
authors.initials: MN
authors.lastname: Niemeijer
authors.affiliation: Department of Medical Informatics, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Marten E
authors.initials: ME
authors.lastname: van den Berg
authors.affiliation: Department of Cardiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Jaap W
authors.initials: JW
authors.lastname: Deckers
authors.affiliation: Department of Internal Medicine, Catharina Hospital, Eindhoven, The Netherlands.
authors.forename: Adrianus L H J
authors.initials: AL
authors.lastname: Aarnoudse
authors.affiliation: Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
authors.affiliation: Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands Department of Internal Medicine, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Medical Informatics, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Rijnbeek
authors.affiliation: Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands Department of Internal Medicine, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Eijgelsheim
authors.affiliation: Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands Department of Internal Medicine, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands Inspectorate of Health Care, Utrecht, The Netherlands.
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D001682:Biological Availability; D016022:Case-Control Studies; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000517:prevention & control*; D004077:Digoxin / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000889:Anti-Arrhythmia Agents; D004077:Digoxin