Allelic variants of MiRP1, including a common polymorphism (T8A-MiRP1), increase the risk of drug-induced long QT syndrome by increasing channel sensitivity to medications like sulfamethoxazole.
Observational (n=98)
Do allelic variants of MiRP1 (KCNE2) contribute to the risk of drug-induced long QT syndrome?
Common, clinically silent sequence variations in the KCNE2 gene can increase the risk of life-threatening drug-induced arrhythmias upon exposure to specific medications like sulfamethoxazole.
p-value: p=<0.0001
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 et al. (Tue,) conducted a observational in Drug-induced long QT syndrome (n=98). KCNE2 gene sequencing and in vitro channel expression vs. Wild-type KCNE2 was evaluated on Decrease in IKr current density compared with wild-type MiRP1 (p=<0.0001). Allelic variants of MiRP1, including a common polymorphism (T8A-MiRP1), increase the risk of drug-induced long QT syndrome by increasing channel sensitivity to medications like sulfamethoxazole.