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

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 journal › Article › peer-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 language	English
Pages (from-to)	10613-10618
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	97
Issue number	19
Publication status	Published - Sep 12 2000

Keywords

Bactrim
LQTS
MiRP1
SNP
Sulfamethoxazole

ASJC Scopus subject areas

Genetics
General

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A common polymorphism associated with antibiotic-induced cardiac arrhythmia. / Sesti, Federico; Abbott, Geoffrey W.; Wei, Jian; Murray, Katherine T.; Saksena, Sanjeev; Schwartz, Peter J.; Priori, Silvia G.; Roden, Dan M.; George, Alfred L.; Goldstein, Steve A N.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 19, 12.09.2000, p. 10613-10618.

Research output: Contribution to journal › Article › peer-review

Sesti, Federico ; Abbott, Geoffrey W. ; Wei, Jian ; Murray, Katherine T. ; Saksena, Sanjeev ; Schwartz, Peter J. ; Priori, Silvia G. ; Roden, Dan M. ; George, Alfred L. ; Goldstein, Steve A N. / A common polymorphism associated with antibiotic-induced cardiac arrhythmia. In: Proceedings of the National Academy of Sciences of the United States of America. 2000 ; Vol. 97, No. 19. pp. 10613-10618.

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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.",

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

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AU - Sesti, Federico

AU - Abbott, Geoffrey W.

AU - Wei, Jian

AU - Murray, Katherine T.

AU - Saksena, Sanjeev

AU - Schwartz, Peter J.

AU - Priori, Silvia G.

AU - Roden, Dan M.

AU - George, Alfred L.

AU - Goldstein, Steve A N

PY - 2000/9/12

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N2 - 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.

AB - 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.

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