Abstract 11082: Exome Sequencing Implicates the Burden of Rare Potassium Channel Variants in the Risk of Drug Induced Long QT Syndrome
Background: Drug-induced long QT syndrome (diLQTS) is associated with the potentially fatal arrhythmia torsades de pointes (TdP). The contribution of rare genetic variants to the underlying genetic framework predisposing diLQTS has not been systematically examined. We tested the hypothesis that rare variants are associated with diLQTS and TdP.
Methods and Results: We performed whole exome sequencing on 65 diLQTS, and 148 drug-exposed controls of European descent. We employed rare variant analyses (the variable threshold [VT] and sequence kernel association test [SKAT]) and gene-set analyses to identify genes enriched with rare amino-acid coding (AAC) variants associated with diLQTS. Significant associations were reanalyzed by comparing cases to 515 ethnically matched controls from the NHLBI GO Exome Sequencing Project (ESP). Rare variants in 23 genes were enriched in the cases according to SKAT or VT compared to either control population, but only KCNE1 and ACN9 were associated with diLQTS in both comparisons (p<0.01). A total of 35% of the diLQTS cases also had ≥1 rare AAC variant, as compared to 21% of controls (p=0.019), in a predefined set of seven congenital LQTS (cLQTS) genes encoding potassium channels or channel modulators (Table).
Conclusions: By combining whole exome sequencing with aggregated rare variant analyses, we implicate rare variants in KCNE1 and ACN9 as risk factors for diLQTS. Moreover, diLQTS cases were more burdened by rare AAC variants in cLQTS genes encoding potassium channel modulators, supporting the idea that multiple rare variants, notably across cLQTS genes, predispose to diLQTS.
- © 2013 by American Heart Association, Inc.