Abstract 16094: RAB3 GTPase Activating Protein Subunit 1 is a Novel Candidate Gene for Sudden Cardiac Death
Introduction: Sudden Cardiac Death (SCD) is a complex trait with an established genetic component and recent genome-wide association studies have identified novel loci associated with SCD. However, identified DNA variants explain relatively little of the overall risk of SCD, suggesting that additional loci remain to be discovered. We hypothesized that use of the MetaboChip custom array would facilitate the discovery of novel genes involved in mechanisms of SCD.
Methods: The MetaboChip custom array includes common and rare DNA variants previously associated with cardiovascular, anthropometric and metabolic traits. We conducted a case-control association study of 119,160 SNPs in 948 SCD cases from the Oregon Sudden Unexpected Death Study (Oregon-SUDS) and 3,050 coronary artery disease controls (CAD) from the Wellcome Trust Case-Control Consortium (WTCCC). Association analyses were performed using logistic regression assuming an additive genetic model adjusting for age, sex and the first 3 dimensions, from multi-dimensional scaling, in PLINK.
Results: The mean age of the investigated individuals in the Oregon-SUDS and the WTCCC studies were 60.8±12.6 and 51.4±7.5 years respectively. A total of 72% of SCD cases and 80.9% of CAD controls were male. We determined a significant P-value cut off of 4.19x10-7given the number of SNPs tested in the study (119,160 SNPs). The most significant SNP was an intronic variant within the RAB3 GTPase activating protein subunit 1(RAB3GAP1) gene (rs6730157, P=1.22x10-14, OR=1.60). Based on in silico replication, we observed an independent association of rs6730157 in the Harvard Cohort SCD Study. The combined P-value of rs6730157 in the discovery and replication samples was 1.27x10-15.
Conclusion: Our findings suggest that RAB3GAP1 is a relevant candidate gene for SCD. This gene is a key regulator of calcium mediated hormone and neurotransmitter exocytosis but further studies will be required to understand the specific biological role of RAB3GAP1 in SCD susceptibility.
- © 2012 by American Heart Association, Inc.