A Common Polymorphism Associated with Antibiotic-Induced Cardiac Arrhythmia

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 IKrthat has been associated previously with inherited LQTS. Here, we examine KCNE2 in 98 patie...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2000-09, Vol.97 (19), p.10613-10618
Main Authors: Sesti, Federico, Abbott, Geoffrey W., Wei, Jian, Murray, Katherine T., Saksena, Sanjeev, Schwartz, Peter J., Priori, Silvia G., Roden, Dan M., George, Alfred L., Steve A. N. Goldstein
Format: Article
Language:English
Subjects:
Action potentials
Amino Acid Sequence
Anatomy & physiology
Animals
Antibiotics
Base Sequence
Biological Sciences
Cardiac arrhythmia
CHO Cells
Cricetinae
DNA Primers
Dysrhythmias
Electric potential
Female
Genetic mutation
Genomics
Humans
Long QT Syndrome - chemically induced
Long QT Syndrome - genetics
Long QT Syndrome - physiopathology
Male
Middle Aged
Missense mutation
Molecular Sequence Data
Mutagenesis
Mutation, Missense
Polymorphism, Single Nucleotide
Potassium
Potassium channels
Potassium Channels - genetics
Potassium Channels, Voltage-Gated
Sulfamethoxazole - adverse effects
Torsades de Pointes
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Summary: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 IKrthat 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.180223197