4q25 and ZFHX3 single nucleotide polymorphisms are associated with electroanatomical characteristics of left atrium and clinical outcomes of radiofrequency catheter ablation in patients with atrial fibrillation

Abstract

Background: Previous studies have demonstrated an association between several single nucleotide polymorphisms and atrial fibrillation (AF). We hypothesized that phenotypes of AF patients were associated with common AF susceptibility alleles.Methods: A total of 659 consecutive patients (57±9 years, 76% male) with paroxysmal (68%) or persistent (32%) AF who underwent catheter ablation and 659 age, sex-matched controls were genotyped for the common AF susceptibility alleles (rs2200733 and rs6843082 at 4q25, rs2106261 at ZFHX3, and rs13376333 at KCNN3). Phenotypes of AF patients including electroanatomical characteristics of left atrium and recurrence after ablation were compared.Results: rs2200733, rs6843082, and rs2106261 genotype distributions were significantly different between the patient and control group (all p<0.001). In contrast, the frequency of rs13376333 genotype was not significantly different between two groups. The rs2200733 variant allele carriers have higher E’ (6.9±2.2 vs. 7.7±2.4 cm/s, p=0.028) and larger left atrium volume (113.5±29.2 vs. 128.5±40.7 mL, p=0.020) than non-variant type. The risk allele of rs2200733 was associated with longer PR interval (185.9±32.6 vs. 174.8±21.9 ms, p=0.018), longer duration of negative P-wave terminal force (57.3±24.3 vs. 48.8±23.9 ms, p=0.018), and higher amplitude of negative P-wave terminal force in Lead V1 (0.07±0.04 vs. 0.05±0.04 mV, p=0.015) on electrocardiography. During 18.8±8.5 months follow-up, rs2106261 at ZFHX3 variant allele carriers had significantly higher recurrence rate than non-variant (Log Rank p=0.017). When the patients were assigned to three groups according to the number of variant alleles (Group A: no variant; n=15, Group B: 1 variant; n=158, Group C: 2 variants; n=439), incremental prognostic value according to the number of variant allele was demonstrated (Log Rank p=0.015).

The multivariate Cox regression analysis showed that persistent AF (OR 1.677, 95% CI 1.176-2.381, p=0.004) and the number of variants (OR 1.552, 95% CI 1.099-2.222, p=0.015) were independent predictors for recurrence of AF.Conclusion: This study showed the common AF susceptibility alleles at 4q25 and ZFHX3 are associated with electroanatomical characteristics of left atrium and clinical outcomes of catheter ablation in Korean patients with AF. These findings imply that gene variants may have a potential role for risk stratification of ablation therapy and post-ablation management.