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Background  Previous studies have suggested  PITX2, KCNN3  and  ZFHX3  as atrial fibrillation (AF) susceptibility genes. Single common genetic polymorphisms of those genes have been linked with AF phenotypes and rhythm outcome of AF catheter ablation although their mechanisms remain elusive. New gene-based association tests may help clarifying genotype–phenotype correlations. Therefore, we hypothesized that  PITX2, KCNN3  and  ZFHX3  associate with left atrial enlargement and persistent AF and subsequently with ablation outcome.    Methods and results  Samples from 660 patients with paroxysmal (n = 370) or persistent AF (n = 290) undergoing AF catheter ablation were genotyped for ~1,000,000 SNPs. Gene-based association was investigated using two different gene-based association tests (VEGAS, minSNP). Among the three candidate genes, only  ZFHX3  associated with left atrial dilatation and AF recurrence after catheter ablation.    Conclusion  This study suggests a contribution of  ZFHX3  to AF remodeling and response to therapy. Future and larger studies are necessary to replicate and apply these findings with an emphasis on designing AF pathophysiology-based multi-locus risk scores.

journal of translational medicine

Association of atrial fibrillation susceptibility genes, atrial fibrillation phenotypes and response to catheter ablation: a gene-based analysis of GWAS data