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Comparative Study
. 2012;7(1):e25387.
doi: 10.1371/journal.pone.0025387. Epub 2012 Jan 11.

Genome-wide association of implantable cardioverter-defibrillator activation with life-threatening arrhythmias

Sarah S Murray  1 , Erin N Smith, Nikki Villarasa, Tara Nahey, Jeff Lande, Harold Goldberg, Marian Shaw, Lawrence Rosenthal, Brian Ramza, Jamshid Alaeddini, Xinqiang Han, Samir Damani, Orhan Soykan, Robert C Kowal, Eric J Topol; GAME Investigators
Affiliations
Comparative Study

Genome-wide association of implantable cardioverter-defibrillator activation with life-threatening arrhythmias

Sarah S Murray et al. PLoS One. 2012.

Abstract

Objectives: To identify genetic factors that would be predictive of individuals who require an implantable cardioverter-defibrillator (ICD), we conducted a genome-wide association study among individuals with an ICD who experienced a life-threatening arrhythmia (LTA; cases) vs. those who did not over at least a 3-year period (controls).

Background: Most individuals that receive implantable cardioverter-defibrillators never experience a life-threatening arrhythmia. Genetic factors may help identify who is most at risk.

Methods: Patients with an ICD and extended follow-up were recruited from 34 clinical sites with the goal of oversampling those who had experienced LTA, with a cumulative 607 cases and 297 controls included in the analysis. A total of 1,006 Caucasian patients were enrolled during a time period of 13 months. Arrhythmia status of 904 patients could be confirmed and their genomic data were included in the analysis. In this cohort, there were 704 males, 200 females, and the average age was 73.3 years. We genotyped DNA samples using the Illumina Human660 W Genotyping BeadChip and tested for association between genotype at common variants and the phenotype of having an LTA.

Results and conclusions: We did not find any associations reaching genome-wide significance, with the strongest association at chromosome 13, rs11856574 at P = 5×10⁻⁶. Loci previously implicated in phenotypes such as QT interval (measure of the time between the start of the Q wave and the end of the T wave as measured by electrocardiogram) were not found to be significantly associated with having an LTA. Although powered to detect such associations, we did not find common genetic variants of large effect associated with having a LTA in those of European descent. This indicates that common gene variants cannot be used at this time to guide ICD risk-stratification.

Trial registration: ClinicalTrials.gov NCT00664807.

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Conflict of interest statement

Competing Interests: Funding for this study was made in part by Medtronic (OS, TN, JL, HG, RCK-consultant), Scripps Health (SSM, EJT, ENS, NV, MS, SD) and NIH/NCRR UL1RR025774 (SSM, SD, EJT). The funders' role in the study pertains to the specific contributions of the authors as listed above, including study design, data collection and analysis, decision to publish and assistance with preparation of the manuscript. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Study design for genome-wide association study of ICD activation with LTA.
Figure 2
Figure 2. Genome-wide association results of Cases with LTA vs. Controls without a LTA.
Association −log(P-values) are plotted according to position in the genome. Points indicate genotyped (circle) or imputed (triangle) SNPs.
See this image and copyright information in PMC

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