PO17 Genome-wide Association Study Uncovers Insights for Prevention of Sudden Cardiac Arrest

Background The genetic basis of sudden cardiac arrest (SCA) remains poorly understood, with only two SCA-associated common variants previously identified, limiting efforts to improve prevention and treatment. We aimed to discover common genetic variants associated with SCA. Methods We conducted genome-wide association studies in 13,462 SCA cases, including 7,052 new samples, of European ancestry from seven studies, four of which required ECG-documented ventricular fibrillation (VF) for inclusion, allowing more precise phenotyping. We performed four successive meta-analyses with increasing phenotype specificity, ranging from any-cause SCA to VF during myocardial infarction (MI), the most common trigger of SCA/VF. Results We identified eight previously unreported loci associated with SCA. Three harbored genes implicated in MI (CDKN2B, LPA, ABO), one contained BAG3, a gene associated with cardiomyopathy, and three (B3GAT1, MKI67, HPCAL4) had no known cardiac associations. A final locus (KCNJ11/ABCC8), which encodes the ATP-sensitive potassium channel (IK-ATP), emerged specifically in cases with VF during MI. IK-ATP channels activate in response to ATP depletion, conferring cardioprotection during ischemia. The risk allele at this locus reduces IK-ATP activity, consistent with pharmacoepidemiologic data showing that sulfonylurea antidiabetics, which block IK-ATP, are associated with higher risks of VF and SCA compared to metformin. Conclusions These findings provide new insights into the genetic architecture of SCA/VF and highlight a possible role for IKATP channel function with potential clinical implications for prevention of SCA/VF in the setting of MI.