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Open Access Highly Accessed Research article

GWAS for discovery and replication of genetic loci associated with sudden cardiac arrest in patients with coronary artery disease

Bradley E Aouizerat1, Eric Vittinghoff2, Stacy L Musone3, Ludmila Pawlikowska4, Pui-Yan Kwok5, Jeffrey E Olgin6 and Zian H Tseng6*

Author Affiliations

1 Department of Physiological Nursing, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143 USA

2 Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94143 USA

3 Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143 USA

4 Department of Anesthesia and Perioperative Care, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143 USA

5 Cardiovascular Research Institute, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143 USA

6 Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143 USA

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BMC Cardiovascular Disorders 2011, 11:29  doi:10.1186/1471-2261-11-29

Published: 10 June 2011

Abstract

Background

Epidemiologic evidence suggests a heritable component to risk for sudden cardiac arrest independent of risk for myocardial infarction. Recent candidate gene association studies for community sudden cardiac arrests have focused on a limited number of biological pathways and yielded conflicting results. We sought to identify novel gene associations for sudden cardiac arrest in patients with coronary artery disease by performing a genome-wide association study.

Methods

Tagging SNPs (n = 338,328) spanning the genome were typed in a case-control study comparing 89 patients with coronary artery disease and sudden cardiac arrest due to ventricular tachycardia or ventricular fibrillation to 520 healthy controls.

Results

Fourteen SNPs including 7 SNPs among 7 genes (ACYP2, AP1G2, ESR1, DGES2, GRIA1, KCTD1, ZNF385B) were associated with sudden cardiac arrest (all p < 1.30 × 10-7), following Bonferroni correction and adjustment for population substructure, age, and sex; genetic variation in ESR1 (p = 2.62 × 10-8; Odds Ratio [OR] = 1.43, 95% confidence interval [CI]:1.277, 1.596) has previously been established as a risk factor for cardiovascular disease. In tandem, the role of 9 genes for monogenic long QT syndrome (LQT1-9) was assessed, yielding evidence of association with CACNA1C (LQT8; p = 3.09 × 10-4; OR = 1.18, 95% CI:1.079, 1.290). We also assessed 4 recently published gene associations for sudden cardiac arrest, validating NOS1AP (p = 4.50 × 10-2, OR = 1.15, 95% CI:1.003, 1.326), CSMD2 (p = 6.6 × 10-3, OR = 2.27, 95% CI:1.681, 2.859), and AGTR1 (p = 3.00 × 10-3, OR = 1.13, 95% CI:1.042, 1.215).

Conclusion

We demonstrate 11 gene associations for sudden cardiac arrest due to ventricular tachycardia/ventricular fibrillation in patients with coronary artery disease. Validation studies in independent cohorts and functional studies are required to confirm these associations.