Novel loci associated with increased risk of sudden cardiac death in the context of coronary artery disease

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: Recent genome-wide association studies (GWAS) have identified novel loci associated with sudden cardiac death (SCD). Despite this progress, identified DNA variants account for a relatively small portion of overall SCD risk, suggesting that additional loci contributing to SCD susceptibility await discovery. The objective of this study was to identify novel DNA variation associated with SCD in the context of coronary artery disease (CAD). METHODS AND FINDINGS: Using the MetaboChip custom array we conducted a case-control association analysis of 119,117 SNPs in 948 SCD cases (with underlying CAD) from the Oregon Sudden Unexpected Death Study (Oregon-SUDS) and 3,050 controls with CAD from the Wellcome Trust Case-Control Consortium (WTCCC). Two newly identified loci were significantly associated with increased risk of SCD after correction for multiple comparisons at: rs6730157 in the RAB3GAP1 gene on chromosome 2 (P = 4.93×10(-12), OR = 1.60) and rs2077316 in the ZNF365 gene on chromosome 10 (P = 3.64×10(-8), OR = 2.41). CONCLUSIONS: Our findings suggest that RAB3GAP1 and ZNF365 are relevant candidate genes for SCD and will contribute to the mechanistic understanding of SCD susceptibility.The Oregon Sudden Unexpected Death Study acknowledges the significant contribution of American Medical Response and the Portland/Gresham fire departments. SSC holds the Pauline and Harold Price Chair in Cardiac Electrophysiology at the Cedars-Sinai Heart Institute. Recruitment of the British Heart Foundation Heart Family Heart Study was funded by the British Heart Foundation (BHF) and the PRAMIS Study by the British Cardiovascular Society. NJS holds a Chair funded by the BHF and is a UK National Institute for Health Research (NIHR) Senior Investigator. This work falls under the portfolio of research conducted within the NIHR Leicester Cardiovascular Biomedical Research Unit. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip