Abstract 18522: Exome Chip Analysis From the CASPER Registry Highlights Potential Genetic Variant Associated With Unexplained Cardiac Arrest

Introduction: The genetics of unexplained cardiac arrest (UCA) remains largely elusive. We sought to identify genetic variants linked to UCA in a case-control genetic association study. Methods: Cases are UCA probands from the Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER), which included individuals with a history of UCA or sudden cardiac death (SCD) with normal autopsy. Exclusion criteria were coronary/structural heart diseases, or a baseline ECG with type I Brugada or prolonged QTc (males>460ms, females>480ms). Controls were individuals without coronary/structural heart diseases, ventricular arrhythmia or family history of SCD, from the Montreal Heart Institute Biobank. We performed exome-wide genotyping using the Illumina HumanExome BeadChip (>250,000 mostly coding markers). Each case was matched with 3 controls from a 3139 individuals dataset using identity-by-descent. Association analysis was performed using the Cochran-Mantel-Haenszel test, controlling for sex. We validated genotyping of most significant variants using Sequenom technology. Results: After quality checks, we compared allele frequencies at 76157 polymorphic markers in 79 cases and 237 matched controls. Genotyping success rate was 99% in both groups. We identified 17 variants with P-values -4 , whereas we would have expected 7 under the null hypothesis of no association. This reflects an enrichment of variants associated with UCA. The strongest association with UCA risk was observed at a single nucleotide polymorphism (SNP) in POLRMT . Minor allele frequency (MAF) in cases and controls was 0.048 and 0.011, respectively (p = 9.7x10 -7 , odds ratio = 5.0). MAF in controls was similar to those reported in Exome Sequence Project (0.014) and 1000 Genomes (0.007). POLRMT encodes a mitochondrial DNA-directed RNA polymerase. Interestingly, POLRMT is located next to HCN2 , which encodes an ion channel previously implicated in ventricular arrhythmia. Conclusion: In this case-control study from the CASPER registry, a SNP in POLMRT is strongly associated with UCA. Replication studies are ongoing. If the association is confirmed, the mechanism of arrhythmogenesis might involve deregulation of gene expression of a nearby ion channel gene.