EARLY REPOLARIZATION PATTERN: CLINICAL CORRELATES OF SPECIFIC ELECTROCARDIOGRAPHIC SUBTYPES AND GENOME WIDE ASSOCIATION STUDY OF A SARDINIAN POPULATION

Abstract Background: An early repolarization (ER) pattern on electrocardiogram (ECG) is common in the general population. ER especially in the inferior distribution has been associated with sudden cardiac death. The aim of this study was to assess clinical correlates and conduct separate preliminary genome wide association studies (GWAS) in subjects with ER and ER subtypes (lateral ER and inferior ER). Methods: ER was defined as J-point elevation >= 0.1mV in >= 2 leads in either lateral (I aVL V4-6) or inferior (II III aVF) lead distribution. ECGs of 5 113 participants from the SardiNIA study an initiative sponsored by the National Institute on Aging were analyzed for ER and categorized into either lateral or inferior distribution. The same individuals were assessed for a range of ECG measurements serum parameters and for 12 500 000 single-nucleotide polymorphisms (SNPs) from sequencing and genotype imputation. Results: ER lateral ER and inferior ER were present in 444 (8.7%) 203 (4.0%) and 241 (4.7%) of 5 113 participants respectively. Male gender younger age and higher Sokolow-Lyon index were associated with ER. Lateral ER subjects were older and more often male than inferior ER subjects. Serum inflammatory markers including erythrocyte sedimentation rate and C-reactive protein were significantly lower in the ER participants driven largely by inferior ER subjects. GWAS of ER lateral ER and inferior ER subjects identified SNPs of genome wide significance (p<5 x 10-8) in genes associated with myocardial infarction a Ca2+ channel and a nitric oxide-inducible gene. Conclusions: ER and ER subtypes have robust association with specific clinical characteristics. GWAS of ER lateral ER and inferior ER in this Sardinian population each yielded SNPs of genome wide significance. Notably lateral ER GWAS localized a SNP to a Ca2+ channel gene previously not reported. The study further suggests heterogeneity of ERP subtypes and may help reconcile the arrhythmogenic difference noted in current literature. Efforts to substantiate these findings and replication are in progress.