Abstract 14459: Genome-Wide Association Analysis Identifies 3 Common Variants Predisposing to Brugada Syndrome, a Rare Disease With High Risk of Sudden Cardiac Death
Introduction: Brugada Syndrome (BrS) is considered as a rare Mendelian disorder with autosomal dominant transmission and is associated with ST-segment elevation in the right precordial leads and an increased risk of sudden cardiac death. SCN5A (NaV1.5) mutations are identified in ~20% of patients. However, studies in families harboring SCN5A mutations have demonstrated low disease penetrance and in some instances absence of the familial SCN5A mutation in some affected members, which suggests a more complex inheritance model.
Methods: To identify common genetic factors modulating disease risk, we conducted a genome-wide association study on 312 individuals with BrS and 1,115 ancestry-matched controls.
Results: Two genomic loci displayed genome-wide significant association. Replication testing on two independent case/control sets from Europe (598/855) and Japan (208/1016) confirmed both associations and revealed a third locus. The cumulative effect of the 3 loci on disease susceptibility was large with an odds ratio of 21.5 in the presence of more than 4 risk alleles versus less than 2.
Two of the three loci had previously been shown to influence ECG conduction parameters in the general population. The third locus encompasses a transcription factor which has not previously been implicated in cardiac electrical function and arrhythmia. Functional studies in knock-out mice for this transcription factor identified differences in expression of NaV1.5, in addition to differences in conduction of the cardiac electrical impulse.
Conclusion: Our findings indicate that common genetic variation may have a strong impact on predisposition to BrS and identify a new gene involved in the pathogenesis of the disease.
- © 2013 by American Heart Association, Inc.