A common polymorphism associated with antibiotic-induced cardiac arrhythmia

TLDR

Drug‑induced long‑QT syndrome is a common, poorly understood disorder that predisposes to sudden death and has been linked to the KCNE2 gene encoding the MiRP1 subunit of the cardiac IKr channel. The study examined KCNE2 in 98 patients with drug‑induced LQTS to identify pathogenic mutations and a common SNP associated with sulfamethoxazole‑induced arrhythmia. Mutant KCNE2 channels had reduced potassium flux, while a common SNP caused normal baseline function but sulfamethoxazole‑mediated inhibition, indicating that MiRP1 variants contribute to drug‑induced LQTS and can remain silent until drug exposure.

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.