Common susceptibility locus associated with ventricular fibrillation and sudden cardiac death

30 July 2010

Sudden cardiac death (SCD) can arise through multiple different molecular mechanisms, and enormous progress has recently been made in understanding genetics factors that increase SCD risk in those with inherited cardiovascular disease (see the PHG Foundation Heart to Heart Report). However, the identification of genetic factors that may determine individuals who are susceptible to SCD in the general population has been limited. As SCD may be the first clinical expression of heart disease in some of these individuals, a greater understanding of the genetic and molecular factors involved may help earlier identification and treatment.

One possible mechanisms of SCD is when a myocardial infarction (MI) leads to ventricular fibrillation (uncoordinated contraction of ventricles). However, not all individuals who have an MI go onto to develop ventricular fibrillation. In order to identify factors that may underlie this difference, Bezzina et al. analysed the genes of 972 individuals with a first acute MI from the Arrhythmia Genetics in The Netherlands (AGNES) study [Bezzina et al. (2010) Nat. Genet. 42(8):688-91]. Of these, 515 individuals had experienced ventricular fibrillation and 457 had not.

The genome-wide association study revealed a SNP (rs2824292) near chromosome 21q21 that reached genome-wide significance associated with ventricular fibrillation. The frequency of this SNP containing the minor allele was found in 53% of cases and 39% of controls, with an odds ratio of 1.78 (95% CI 1.47-2.13). This association was replicated in an independent MI case-control set from the Amsterdam Resuscitation Study- Myocardial Infarction (ARREST-MI) study, consisting of 146 out-of hospital individuals with MI complicated by ventricular fibrillation and 391 individuals who had survived an MI.

The gene closest to this SNP is CXADR, which encodes a viral receptor that has been implicated in pathogenesis of viral myocarditis. The authors suggest that this is a novel candidate gene for arrhythmia susceptibility, and are aiming to conduct further studies into the influence of the genotype at rs2824292 on its expression.


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