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 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.
Sesti
F
F
Departments of Pediatrics and Cellular and Molecular Physiology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06536, USA.
Abbott
G W
GW
Wei
J
J
Murray
K T
KT
Saksena
S
S
Schwartz
P J
PJ
Priori
S G
SG
Roden
D M
DM
George
A L
AL
Goldstein
S A
SA
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D017931:DNA Primers; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016296:Mutagenesis; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D013420:Sulfamethoxazole / Q000009:adverse effects*
D017931:DNA Primers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk); D013420:Sulfamethoxazole