Abstract
BackgroundPrevious 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 resultsSamples 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.ConclusionThis 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.
Highlights
Previous studies have suggested PITX2, KCNN3 and ZFHX3 as atrial fibrillation (AF) susceptibility genes
For the first time, we apply gene-based analysis of genome-wide association studies (GWAS) data to test the hypothesis that AF candidate genes PITX2, KCNN3 and ZFHX3 associate with left atrial enlargement and persistent AF and subsequently with arrhythmia recurrence following AF catheter ablation
Left atrial diameter (LAD) was significantly larger in patients with persistent AF (41 ± 5 vs. 45 ± 6 mm, P < 1.0E−3) compared to patients with paroxysmal AF
Summary
Previous studies have suggested PITX2, KCNN3 and ZFHX3 as atrial fibrillation (AF) susceptibility genes. Single nucleotide polymorphisms (SNPs) at chromosomes 4q25 (PITX2) [1, 2], 16q22 (ZFHX3) [3], and 1q21 (KCNN3) [4] have been shown to associate with atrial fibrillation (AF) in different genome-wide association studies (GWAS). Linkage disequilibrium (LD) structure and genotyping coverage may impact on GWAS results when only analyzing single SNPs. gene-based association tests have been introduced that are well-suited to identify genes that may increase susceptibility to complex diseases, phenotypes and response to therapy. Gene-based association tests have been introduced that are well-suited to identify genes that may increase susceptibility to complex diseases, phenotypes and response to therapy They have been designed to detect genes that are genome-wide
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