Abstract 13222: Genetic Variants Close to NKX2-5 and MYH6 Are Associated With AV Nodal Reentry Tachycardia in First Genome-Wide Association Study

Abstract

Introduction: AV nodal re-entry tachycardia (AVNRT) is the most common type of paroxysmal supraventricular tachycardia. At present, the underlying etiology of AVNRT is unclear. Hypothesis: In a genome-wide association study (GWAS), we aimed to identify common genetic variants associated with AVNRT. Methods: We performed a GWAS meta-analysis of Danish patients diagnosed with AVNRT verified by invasive electrophysiological study. An Icelandic population of AVNRT patients was used for replication. We performed conditional analysis by adjusting our analysis for atrial fibrillation (AF) genetics and transcriptome-wide analyses (TWAS) to assess associations between gene expression and AVNRT. Electrophysiological consequences were investigated in CRISPR-Cas9 modified zebrafish. Results: A total of 1,515 AVNRT patients and 38,428 controls were available for meta-analysis. Two genetic loci associated with AVNRT; at chromosome 5q35.1, close to the NKX2-5 gene (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.38-1.58, P = 2.6 х 10 -13 ), and at 14q11.2 in the MYH6 gene (OR 1.26, 95% CI 1.18-1.34, P = 2.3 х 10 -8 ). We found similar effect sizes and direction of effect for both loci in the Icelandic AVNRT cohort. Using conditional analyses, we found that these loci were associated with AVNRT independent of AF. Analyses of loss of Nkx2-5 zebrafish showed no difference with regards to electrocardiographic parameters and transmission electron microscopy of atrial tissue compared with wildtype. Conclusion: This is, to our knowledge, the first GWAS on AVNRT. We identified two genetic loci that associated with AVNRT.