Abstract 18723: Genetic Variants Associated with QT Prolongation in Patients Exposed to Sotalol: A Genome Wide Association Study
Introduction Sotalol is a frequently used antiarrhythmic drug known to cause QT-prolongation and increase the risk of the malignant arrhythmia Torsades de Pointes. We performed a genome wide association study (GWAS) to identify genetic markers associated with QT prolongation in sotalol exposed patients who were followed in an electronic medical record (EMR) system.
Methods We identified 404 consented European American patients who initiated sotalol treatment via an EMR system through 2001-2011. Genotpying was performed on the Illumina 610-Quad BeadChip or the Illumina Human OMNI-express BeadChip, and the set of single nucleotide polymorphisms (SNPs) common to the two were analyzed initially. Maximum QT intervals were evaluated before and ≥48 hours after the start of therapy. Tests of association using linear regression were performed for change in the QTc interval assuming an additive genetic model adjusted for age and sex.
Results After quality control, we analyzed a total of 314,618 SNP’s with a minor allele frequency of >1% and a call rate of ≥98%. The strongest associations were found for SNPs harbored in genes FAM107B (p= 2.09E-07), NRG-3 (p=1.94E-06), and SVEP (p=6.44E-06). NRG-3 is involved in cardiac development and has previously been associated with QT prolongation. The estimated effect size of the top SNP in NRG-3 (rs7073972) is 12.3ms with a MAF=27%. FAM107B encode proteins of unknown function and SVEP encodes membrane proteins involved in cell adhesion processes. Both are expressed in cardiac tissue although neither has previously been associated with cardiac electrophysiology.
Conclusion This GWAS identified genetic markers associated with change in the QTc interval during sotalol treatment. Notably, NRG-3 has previously been linked to drug induced QT interval prolongation. The results of this pharmacogenomics study provide novel insight into the clinical response to sotalol with the ultimate goal of directing therapy of future patients.
- © 2012 by American Heart Association, Inc.