A common polymorphism associated with antibiotic-induced cardiac arrhythmia

Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10613-8. doi: 10.1073/pnas.180223197.


Drug-induced long QT syndrome (LQTS) is a prevalent disorder of uncertain etiology that predisposes to sudden death. KCNE2 encodes MinK-related peptide 1 (MiRP1), a subunit of the cardiac potassium channel I(Kr) that has been associated previously with inherited LQTS. Here, we examine KCNE2 in 98 patients with drug-induced LQTS, identifying three individuals with sporadic mutations and a patient with sulfamethoxazole-associated LQTS who carried a single-nucleotide polymorphism (SNP) found in approximately 1.6% of the general population. While mutant channels showed diminished potassium flux at baseline and wild-type drug sensitivity, channels with the SNP were normal at baseline but inhibited by sulfamethoxazole at therapeutic levels that did not affect wild-type channels. We conclude that allelic variants of MiRP1 contribute to a significant fraction of cases of drug-induced LQTS through multiple mechanisms and that common sequence variations that increase the risk of life-threatening drug reactions can be clinically silent before drug exposure.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • CHO Cells
  • Cricetinae
  • DNA Primers
  • Female
  • Humans
  • Long QT Syndrome / chemically induced*
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / physiopathology
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutagenesis
  • Mutation, Missense
  • Polymorphism, Single Nucleotide*
  • Potassium Channels / genetics*
  • Potassium Channels, Voltage-Gated*
  • Sulfamethoxazole / adverse effects*


  • DNA Primers
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • potassium channel protein I(sk)
  • Sulfamethoxazole