A common polymorphism associated with antibiotic-induced cardiac arrhythmia.

Sesti F, Abbott GW, Wei J, Murray KT, Saksena S, Schwartz PJ, Priori SG, Roden DM, George AL, Goldstein SA
Proc Natl Acad Sci U S A. 2000 97 (19): 10613-8

PMID: 10984545 · PMCID: PMC27073 · 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.

MeSH Terms (18)

Amino Acid Sequence Animals Base Sequence CHO Cells Cricetinae DNA Primers Female Humans Long QT Syndrome Male Middle Aged Molecular Sequence Data Mutagenesis Mutation, Missense Polymorphism, Single Nucleotide Potassium Channels Potassium Channels, Voltage-Gated Sulfamethoxazole

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