Genome-Wide Association of Implantable Cardioverter-Defibrillator Activation With Life-Threatening Arrhythmias

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

Molecular genetics of atrial fibrillation

Atrial fibrillation (AF) is the most common persistent cardiac dysrhythmia and the number one cause of arrhythmia-related hospitalizations. In addition, AF is a major contributor to stroke. With life expectancies increasing, the growing global disability from AF has crippling implications for society. Several family studies have shown a strong polygenetic predisposition for AF but, so far, most of the linkage analysis and candidate gene studies have discovered only monogenic, rare, deleterious mutations. Recent breakthroughs in high-throughput genotyping technology have allowed improved scanning of the genome with greater statistical power to detect susceptibility alleles for AF. Using this technology, a region on 4q25 has now been identified and validated in thousands of cases as a common susceptibility factor for AF with an odds ratio of over 3.0 for homozygotes. The Paired-like homeodomain transcription factor 2 (PITX2) gene, which is involved in embryonic cardiac development, has now been identified as the causal variant for the 4q25 susceptibility locus. Additional susceptibility variants are anticipated that will have direct ramifications for prognosis and treatment of this highly pervasive and clinically significant disorder

Electrophysiological characteristics of cases and controls.

<p>Electrophysiological characteristics of cases and controls.</p

Genome-wide association results of Cases with LTA vs. Controls without a LTA.

<p>Association −log(P-values) are plotted according to position in the genome. Points indicate genotyped (circle) or imputed (triangle) SNPs.</p

Top regions associated at P<10⁻⁵.

<p>*imputed; #SNPs at P<10⁻⁴ indicates the number of SNPs at P<10⁻⁴ within +/−150 kb of the top SNP that were either directly genotyped or imputed (genotyped/imputed).</p

Baseline use of key medications.

<p>Baseline use of key medications.</p

Study design for genome-wide association study of ICD activation with LTA.

<p>Study design for genome-wide association study of ICD activation with LTA.</p

Demographics of Cases and Controls at Time of ICD Implantation.

<p>Demographics of Cases and Controls at Time of ICD Implantation.</p