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ABCB1 gene variants, digoxin and risk of sudden cardiac death in a general population
  1. Maartje N Niemeijer1,
  2. Marten E van den Berg2,
  3. Jaap W Deckers3,
  4. Adrianus L H J Aarnoudse4,
  5. Albert Hofman1,
  6. Oscar H Franco1,
  7. André G Uitterlinden1,5,
  8. Peter R Rijnbeek2,
  9. Mark Eijgelsheim1,5,
  10. Bruno H Stricker1,5,6
  1. 1Department of Epidemiology, Erasmus MC—University Medical Center Rotterdam, Rotterdam, The Netherlands
  2. 2Department of Medical Informatics, Erasmus MC—University Medical Center Rotterdam, Rotterdam, The Netherlands
  3. 3Department of Cardiology, Erasmus MC—University Medical Center Rotterdam, Rotterdam, The Netherlands
  4. 4Department of Internal Medicine, Catharina Hospital, Eindhoven, The Netherlands
  5. 5Department of Internal Medicine, Erasmus MC—University Medical Center Rotterdam, Rotterdam, The Netherlands
  6. 6Inspectorate of Health Care, Utrecht, The Netherlands
  1. Correspondence to Professor Bruno H Stricker, Department of Epidemiology, Erasmus MC—University Medical Center Rotterdam; PO Box 2040, Rotterdam 3000CA, The Netherlands; b.stricker{at}erasmusmc.nl

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.

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