A common polymorphism associated with antibiotic-induced cardiac arrhythmia

Federico Sesti, Geoffrey W. Abbott, Jian Wei, Katherine T. Murray, Sanjeev Saksena, Peter J. Schwartz, Silvia G. Priori, Dan M. Roden, Alfred L. George, Steve A N Goldstein

Research output: Contribution to journalArticlepeer-review

Abstract

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 ≃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.

Original languageEnglish
Pages (from-to)10613-10618
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number19
Publication statusPublished - Sep 12 2000

Keywords

  • Bactrim
  • LQTS
  • MiRP1
  • SNP
  • Sulfamethoxazole

ASJC Scopus subject areas

  • Genetics
  • General

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