A Large Candidate Gene Survey Identifies the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes

Abstract

Background Drug-induced long QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. Here, we tested the hypothesis that common variants in key genes controlling cardiac electrical properties modify the risk of diLQTS. Methods and Results In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 msec QT lengthening during initiation of therapy with a QT-prolonging drug, and 837 controls from the population based KORA study. Subjects were successfully genotyped at 1,424 single nucleotide polymorphisms (SNPs) in 18 candidate genes including 1,386 SNPs tagging common haplotype blocks, and 38 non-synonymous ion channel gene SNPs. For validation we used a set of cases (n=57) and population-based controls of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval: 3.5–22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed controls, and 1.8% of population controls. In the validation cohort the variant allele was present in 3.5% of cases, and in 1.4% of controls. Conclusions This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.

A novel genetic modifier for clarithromycin-related cardiac arrhythmia risk?

“…A recent candidate gene survey found the D85N KCNE1 polymorphism in 8.6% of drug-induced long QT syndrome cases, compared with less than 2% of controls [Kaab et al 2012], with other smaller studies also providing evidence of an association [Paulussen et al 2004;Lin et al 2012]. This association underscores the potential value of genetic screening in drug-induced long QT syndrome/TdP, whilst our recent data on clarithromycin highlight a potential new mechanism for individual variation in clarithromycin sensitivity [Du et al 2013].…”

Exome Sequencing Implicates an Increased Burden of Rare Potassium Channel Variants in the Risk of Drug-Induced Long QT Interval Syndrome

“…We then attempted to replicate those associations using the diLQTS cases vs. 515 population controls from the ESP using both VT and SKAT aggregate analyses (p<0.05); this use of two control populations, one drug-exposed and one drawn from a general population, is similar to that we previously employed in a candidate diLQTS analysis (7). We only considered genes to be significantly associated with diLQTS if they: i) passed the p<0.001 cut-off in both types of rare variant analyses (VT and SKAT) comparing diLQTS cases and drug-exposed controls); and ii) replicated using the diLQTS cases vs. ESP population controls.…”

“…In addition, first degree relatives of patients with diLQTS have been reported to display exaggerated responses to challenge with the QT prolonging agent quinidine (4). These observations, coupled with the widely-held view that adverse drug reactions (ADR) include a genomic component (5,6), have led to searches for DNA variants predisposing to diLQTS (7-9). Mutations in cLQTS disease genes have been reported in up to 36-40% of diLQTS patients (10,11), consistent with the notion that drug challenge may expose the congenital form of the syndrome (12).…”

“…Mutations in cLQTS disease genes have been reported in up to 36-40% of diLQTS patients (10,11), consistent with the notion that drug challenge may expose the congenital form of the syndrome (12). In a recent study interrogating genetic predisposition to diLQTS using 1424 tag single nucleotide polymorphisms (SNPs) in 18 genes, the KCNE1 missense polymorphism resulting in D85N conferred an odds ratio of 9.0 for diLQTS (7). A genome-wide association study has not identified strong associations between common polymorphisms and diLQTS (13).…”

Unveiling Specific Triggers and Precipitating Factors for Fatal Cardiac Events in Inherited Arrhythmia Syndromes

“…[39][40][41][42][43] Of note, functional analysis revealed that KCNQ1 or KCNH2 mutations identified in dLQTS showed no dominant-negative suppression or only a relatively mild decreased current density compared with those identified in congenital LQTS (cLQTS). 42 Drugs that have an IKr-blocking effect lead to further reductions of the repolarizing currents in patients with a latent genetic background of mildly reduced repolarizing currents, thus unmasking dLQTS.…”