Abstract 16410: Identification of Novel Genetic Markers Associated with Lethal Ventricular Arrhythmias in Heart Failure Patients: Genome Wide Association Study in the DISCERN cohort
Background: Sudden Cardiac Death due to arrhythmic events may have a strong genetic component. We performed a genome-wide association study to identify genetic factors associated with ventricular arrhythmia in a primary prevention heart failure (HF) population with implantable cardioverter-defibrillators (ICDs).
Methods: DNA was isolated from 658 patients (82.8% male, 76% ischemic HF, mean ejection fraction 26.4% ± 8.4) enrolled in DISCERN, a multi-center clinical trial (NCT00500708) designed to identify genetic loci associated with ventricular tachycardia or fibrillation (VT or VF). Of the 658 patients, 234 had an adjudicated appropriate ICD therapy for VT or VF after ICD implant. DNA was genotyped using the Affymetrix SNP 6.0 platform.
Results: A total of 748,158 SNPs with minor allele frequency >0.01 and call rate of >95% were analyzed. Genotype association of time from ICD implant to first event or the end of the observation period was assessed after correction for significant clinical variables. One SNP located at 4q22 (rs17024266) achieved genome-wide significance (p=7.96x10−08, p<.015, corrected for the effective number of tests, with a hazard ratio of 2.64 (95% CI 1.85 - 3.76) for VT or VF. This SNP is located ∼70 Kb upstream from UNC5C, a gene with a role in axon extension during neural development. Using a false-discovery rate cut-off of 50%, an additional 47 loci, many of which associated with sympathetic innervation pathways, were identified as candidates for further investigation.
Conclusions: In this study, a SNP located at 4q22 was significantly associated with time to VT or VF in patients with cardiomyopathy, suggesting it is possible to identify common genetic variants associated with lethal ventricular arrhythmias. Replication of these findings in new cohorts will be necessary to validate these results, and to potentially develop methodology for better risk stratification of HF patients for primary prevention ICD implantation.
- Ventricular arrhythmia
- Risk factors
- Implantable cardioconvert defibrillator
- Sudden cardiac death
- © 2010 by American Heart Association, Inc.