A common polymorphism associated with antibiotic-induced cardiac arrhythmia

Area of Science:

• Cardiovascular Genetics
• Pharmacogenomics
• Ion Channel Physiology

Background:

• Drug-induced long QT syndrome (LQTS) is a significant cause of sudden cardiac death with complex origins.
• KCNE2 gene encodes the MinK-related peptide 1 (MiRP1) subunit of the cardiac potassium channel I(Kr), implicated in inherited LQTS.

Purpose of the Study:

• To investigate the role of KCNE2 variants in patients diagnosed with drug-induced LQTS.
• To determine the functional consequences of identified KCNE2 mutations and single-nucleotide polymorphisms (SNPs) on cardiac potassium channel function and drug response.

Main Methods:

• Genetic analysis of the KCNE2 gene in 98 patients with drug-induced LQTS.
• Functional characterization of mutant and SNP-carrying channels using electrophysiology to assess potassium flux and drug sensitivity.
• Comparison of wild-type and variant channel behavior in response to therapeutic drug levels.

Main Results:

• Three patients with sporadic mutations in KCNE2 were identified.
• One patient with sulfamethoxazole-associated LQTS carried a common KCNE2 SNP (rs number not provided).
• Mutant channels exhibited reduced baseline potassium current, while SNP-carrying channels were inhibited by sulfamethoxazole at therapeutic concentrations, unlike wild-type channels.

Conclusions:

• Allelic variants of MiRP1 (encoded by KCNE2) are a significant contributing factor to drug-induced LQTS through diverse mechanisms.
• Common KCNE2 sequence variations can predispose individuals to life-threatening drug reactions, remaining asymptomatic prior to drug exposure.