A common polymorphism associated with antibiotic-induced cardiac arrhythmia

A common polymorphism associated with antibiotic-induced cardiac arrhythmia

^*Departments of Pediatrics and Cellular and Molecular Physiology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06536; ^†Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, TN 37235; ^‡Robert Wood Johnson Medical School, Passaic, NJ 07055; and ^§Department of Cardiology, University of Pavia and Policlinico San Matteo IRCCS, Pavia, Italy 27100

Edited by Vincent T. Marchesi, Yale University School of Medicine, New Haven, CT, and approved July 6, 2000 (received for review May 16, 2000)

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.

Footnotes

↵ ¶ To whom reprints should be addressed at: Yale University, BCMM, 295 Congress Avenue, New Haven, CT 06536. E-mail: steve.goldstein{at}yale.edu.
This paper was submitted directly (Track II) to the PNAS office.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.180223197.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.180223197
Abbreviations:

LQTS,

long QT syndrome;

MiRP1,

MinK-related peptide 1;

SNP,

single-nucleotide polymorphism;

TdP,

torsades de pointes;

TMP/SMX,

trimethoprim/sulfamethoxazole;

CHO,

Chinese hamster ovary