Editors' ChoiceCardiovascular Disease

Decoding Sudden Cardiac Death

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Science Translational Medicine  21 Jul 2010:
Vol. 2, Issue 41, pp. 41ec115
DOI: 10.1126/scitranslmed.3001483

Cardiovascular disease remains the leading cause of death worldwide despite recent advances in prevention and treatment. More than 50% of these deaths are secondary to tachyarrhythmias such as ventricular fibrillation. To date, there has been no accurate way to identify those individuals at greatest risk for a lethal arrhythmia. Now, a recent genome-wide association study (GWAS) offers hope for the development of such a predictive biomarker by identifying genomic variants strongly associated with ventricular fibrillation.

In the first stage of the study, Bezzina et al. assayed over 500,000 single-nucleotide polymorphisms (SNPs) in 515 individuals with ventricular fibrillation and myocardial infarction and 457 controls with myocardial infarction alone. Surprisingly, the most significant associated SNP, rs2824292 (P = 3.3 × 10–10), was present in 53% of the individuals with ventricular fibrillation and conferred an impressive 180% increase in risk for ventricular fibrillation. This association was then validated in a separate study of over 500 cases and controls. One other protective allele in an independent chromosomal region was also identified in the GWAS (P = 3.34 × 10–7) but fell short of significance in the validation study (P = 0.057). Notably, the SNP rs2824292 is located near the gene CXADR, which encodes the coxsackievirus and adenovirus receptor protein. This transmembrane tight junction protein has been previously implicated in both virus-mediated cardiomyopathies and in sudden cardiac death in candidate gene-based studies.

Thus, in contrast to the modest effects and unknown functional significance of most SNPs identified through GWAS, this seminal study has identified a susceptibility locus with a striking effect in a genomic region with plausible biologic relevance. Additional studies will need to be performed to precisely define the functional basis for this variant’s impact on the risk for sudden cardiac death. Nevertheless, the genomic underpinnings of ventricular fibrillation illuminated by this study will very likely lead to better predictive algorithms and new therapies in the future.

C. R. Bezzina et al., Genome-wide association study identifies a susceptibility locus at 21q21 for ventricular fibrillation in acute myocardial infarction. Nat. Genet. 11 July 2010 (10.1038/ng.623). [Abstract]

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