A large candidate gene survey identifies the KCNE1D85N polymorphism as a possible modulator of drug-induced torsades de pointes

Stefan Kääb, Dana C. Crawford, Moritz F. Sinner, Elijah R. Behr, Prince J. Kannankeril, Arthur A M Wilde, Connie R. Bezzina, Eric Schulze-Bahr, Pascale Guicheney, Nanette Bishopric, Robert J Myerburg, Jean Jacques Schott, Arne Pfeufer, Britt Maria Beckmann, Eimo Martens, Taifang Zhang, Birgit Stallmeyer, Sven Zumhagen, Isabelle Denjoy, Abdennasser BardaiIsabelle C. Van Gelder, Yalda Jamshidi, Chrysoula Dalageorgou, Vanessa Marshall, Steve Jeffery, Saad Shakir, A. John Camm, Gerhard Steinbeck, Siegfried Perz, Peter Lichtner, Thomas Meitinger, Annette Peters, H. Erich Wichmann, Christiana Ingram, Yuki Bradford, Shannon Carter, Kris Norris, Marylyn D. Ritchie, Alfred L. George, Dan M. Roden

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

Background-Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. Methods and Results-In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT-prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed +50 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population-based KORA study. Subjects were successfully genotyped at 1424 single-nucleotide polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval, 3.5-22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects. Conclusions-This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.

Original languageEnglish
Pages (from-to)91-99
Number of pages9
JournalCirculation: Cardiovascular Genetics
Volume5
Issue number1
DOIs
StatePublished - Feb 1 2012

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Keywords

  • Adverse drug events
  • Candidate genes
  • Death, sudden
  • SNP
  • Torsade de pointes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

Cite this

Kääb, S., Crawford, D. C., Sinner, M. F., Behr, E. R., Kannankeril, P. J., Wilde, A. A. M., Bezzina, C. R., Schulze-Bahr, E., Guicheney, P., Bishopric, N., Myerburg, R. J., Schott, J. J., Pfeufer, A., Beckmann, B. M., Martens, E., Zhang, T., Stallmeyer, B., Zumhagen, S., Denjoy, I., ... Roden, D. M. (2012). A large candidate gene survey identifies the KCNE1D85N polymorphism as a possible modulator of drug-induced torsades de pointes. Circulation: Cardiovascular Genetics, 5(1), 91-99. https://doi.org/10.1161/CIRCGENETICS.111.960930