Association of Single Nucleotide Polymorphisms with Atrial Fibrillation and the Outcome after Catheter Ablation.
ABSTRACT: BACKGROUND:The association of gene variants with atrial fibrillation (AF) type and the recurrence of AF after catheter ablation in Taiwan is still unclear. In this study, we aimed to investigate the relationships between gene variants, AF type, and the recurrence of AF. METHODS:In our investigation, we examined 383 consecutive patients with AF (61.9 ± 14.0 years; 63% men); of these 383 patients, 189 underwent catheter ablation for drug-refractory AF. Thereafter, the single nucleotide polymorphisms rs2200733, and rs7193343 were genotyped using real-time polymerase chain reaction. RESULTS:The rs7193343 variant was independently associated with non-paroxysmal AF (non-PAF). In the PAF group, the rs7193343 variant was independently associated with AF recurrence after catheter ablation. However, the rs2200733 variant was not associated with AF recurrence in this group. The combination of the rs7193343 and rs2200733 risk alleles was associated with a better predictive power in the PAF patients. In contrast, in the non-PAF group, the SNPs were not associated with recurrence. The rs7193343 and rs2200733 variants were not associated with different atrial voltage and activation times. CONCLUSIONS:The rs7193343 variants were associated with AF recurrence after catheter ablation in PAF patients but not in non-PAF patients. The rs7193343 CC variant was independently associated with non-PAF.
Project description:Recent studies suggested that variants on chromosome loci 4q25, 1q21, and 16q22 were associated with atrial fibrillation recurrence after catheter ablation. In this study, we performed a systematic review and meta-analysis to explore the association between variants on chromosome loci 4q25, 1q21, and 16q22 and atrial fibrillation recurrence after catheter ablation.We comprehensively searched the databases of MEDLINE and EMBASE from inception to January 2017. Included studies were published prospective or retrospective cohort and case control studies that compared the risk of atrial fibrillation recurrence after catheter ablation in AF patients with chromosome 4q25, 1q21, and 16q22 variants versus no variants. Single-nucleotide polymorphism rs1906617, rs2106261, rs7193343, rs2200733, rs10033464, rs13376333, and rs6843082 were included in this analysis. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate the risk ratios and 95% confidence intervals.Seven studies from January 2010 to June 2017 involving 3,322 atrial fibrillation patients were included in this meta-analysis. According to the pooled analysis, there was a strong independent association between chromosome 4q25 variant (rs2200733) and the risk of atrial fibrillation recurrence after catheter ablation (risk ratio 1.45 [95% confidence interval 1.15-1.83], P = 0.002). No association was found in other variants.Our meta-analysis demonstrates a statistically significant increased risk of atrial fibrillation recurrence after catheter ablation in 4q25 variant (only in rs2200733) but not in 1q21 or 16q22 variants.
Project description:Common single nucleotide polymorphisms (SNPs) at chromosomes 4q25 (rs2200733, rs10033464 near PITX2), 1q21 (rs13376333 in KCNN3), and 16q22 (rs7193343 in ZFHX3) have consistently been associated with the risk of atrial fibrillation (AF). Single-center studies have shown that 4q25 risk alleles predict recurrence of AF after catheter ablation of AF. Here, we performed a meta-analysis to test the hypothesis that these 4 AF susceptibility SNPs modulate response to AF ablation.Patients underwent de novo AF ablation between 2008 and 2012 at Vanderbilt University, the Heart Center Leipzig, and Massachusetts General Hospital. The primary outcome was 12-month recurrence, defined as an episode of AF, atrial flutter, or atrial tachycardia lasting >30 seconds after a 3-month blanking period. Multivariable analysis of the individual cohorts using a Cox proportional hazards model was performed. Summary statistics from the 3 centers were analyzed using fixed effects meta-analysis. A total of 991 patients were included (Vanderbilt University, 245; Heart Center Leipzig, 659; and Massachusetts General Hospital, 87). The overall single procedure 12-month recurrence rate was 42%. The overall risk allele frequency for these SNPs ranged from 12% to 35%. Using a dominant genetic model, the 4q25 SNP, rs2200733, predicted a 1.4-fold increased risk of recurrence (adjusted hazard ratio,1.3 [95% confidence intervals, 1.1-1.6]; P=0.011). The remaining SNPs, rs10033464 (4q25), rs13376333 (1q21), and rs7193343 (16q22) were not significantly associated with recurrence.Among the 3 genetic loci most strongly associated with AF, the chromosome 4q25 SNP rs2200733 is significantly associated with recurrence of atrial arrhythmias after catheter ablation for AF.
Project description:<h4>Background</h4>This study evaluated the status of single nucleotide polymorphisms (SNPs) in Korean patients with early-onset (< 40 years old) atrial fibrillation (AF) and their effects on the outcome after catheter ablation.<h4>Methods</h4>A total of 89 patients (35.7 ± 3.7 years, 81 males) with drug-refractory AF (paroxysmal 64.0%) who underwent catheter ablation were included in this study. Sixteen SNPs, including rs13376333, rs10465885, rs10033464, rs2200733, rs17042171, rs6843082, rs7193343, rs2106261, rs17570669, rs853445, rs11708996, rs6800541, rs251253, rs3807989, rs11047543, and rs3825214, were genotyped. Serial 48-hour Holter monitoring was conducted to detect AF recurrences during long-term follow up.<h4>Results</h4>Wild-type genotypes of rs11047543 (GG; 26/69 [37.7%] vs. GA; 13/18 [72.2%] vs. AA; 0/0 [0%], <i>P</i> = 0.009) and rs7193343 (CC; 0/7 [0%] vs. CT; 22/40 [55.0%] vs. TT; 18/41 [43.9%], <i>P</i> = 0.025) and the homozygous variant of rs3825214 (AA; 16/31 [51.6%] vs. AG; 22/43 [51.2%] vs. GG; 2/13 [15.4%], <i>P</i> = 0.056) were significantly associated with a lower rate of late recurrence. When the patients were assigned to four groups according to the number of risk alleles (n = 0-3), there were significant differences in recurrence rate (n = 0; 0/3 vs. n = 1; 2/13 [15.4%] vs. n = 2; 24/52 [46.2%] vs. n = 3; 13/17 [76.5%], <i>P</i> = 0.003). When correcting for multiple variables, rs11047543 (hazard ratio [HR], 2.723; 95% confidence interval [CI], 1.358-5.461; <i>P</i> = 0.005) and the number of risk alleles (HR, 2.901; 95% CI, 1.612-5.219; <i>P</i> < 0.001) were significantly associated with recurrence of AF after catheter ablation.<h4>Conclusion</h4>Polymorphisms on rs7193343 closest to ZFHX3 (16q22), rs3825214 near to TBX5 (12q24), and rs11047543 near to SOX5 (12p12) modulate the risk for AF recurrence after catheter ablation. The number of risk alleles of these 3 SNPs was an independent predictor of recurrence during long-term follow up in Korean patients with early-onset AF.
Project description:BACKGROUND:Genome-wide studies have shown that polymorphisms on chromosome 4q25, 16q22 and 1q21 correlate with atrial fibrillation (AF). However, the distribution of these polymorphisms differs significantly among populations. OBJECTIVE:To test the polymorphisms on chromosome 4q25, 16q22 and 1q21 in a group of patients (pts) that underwent catheter ablation of AF. METHODS:Four hundred and ten patients with AF that underwent pulmonary vein isolation were included in the study. Control group (n?=?550) was taken from healthy population, matched for age, sex and presence of hypertension. All participants were genotyped for the presence of the rs2200733, rs10033464, rs17570669, rs3853445, rs6838973 (4q25), rs7193343 (16q22) and rs13376333 (1q21) polymorphisms. RESULTS:All the polymorphisms tested (except rs17570669) correlated significantly with AF in univariate analysis (p values between 0.039 for rs7193343 and 2.7e-27 for rs2200733), with the odds ratio (OR) 0.572 and 0.617 for rs3853445 and rs6838973, respectively (protective role) and OR 1.268 to 3.52 for the other polymorphisms. All 4q25 SNPs tested but rs3853445 were independently linked with AF in multivariate logistic regression analysis. In haplotype analysis six out of nine 4q25 haplotypes were significantly linked with AF. The T allele of rs2200733 favoured increased number of episodes of AF per month (p?=?0.045) and larger pulmonary vein diameter (recessive model, p?=?0.032). CONCLUSIONS:Patients qualified for catheter ablation of AF have a significantly higher frequency of 4q25, 16q22 and 1q21 variants than the control group. The T allele of rs2200733 favours larger pulmonary veins and increased number of episodes of AF.
Project description:To test polymorphisms rs2200733 (chromosome 4q25) and rs2106261 (ZFHX3) were associated with AF recurrence after catheter ablation in a Chinese Han cohort. A total of 235 AF patients who underwent catheter ablation were recruited consecutively. Two polymorphisms were amplified by polymerase chain reaction and genotyped using high resolution melting analysis. Primary endpoints for AF recurrence were defined as the time to the first recurrence of atrial tachycardia/flutter/fibrillation (AT/AF). AT/AF recurrence was observed in 76 patients (35%). Allelic analysis demonstrated that rs2200733 was strongly associated with AF recurrence after ablation (P = 0.011) and the minor allele T increased the risk for recurrence (OR = 1.715). Diameters of the right atrium as well as the left and right superior pulmonary veins (PVs) were associated with rs2200733 in different genetic models (P = 0.040, 0.047 and 0.028, respectively). No significant association was detected between rs2106261 and AT/AF recurrence after ablation or atrial/PV diameters in any models. On multivariate Cox regression analysis, only rs2200733 was an independent factor of AF recurrence after ablation (HR = 0.532, P = 0.022). In Chinese Han population, rs2200733 but not rs2106261 is associated with AT/AF recurrence after ablation. The patients with genotype TT have larger size of right atrium and superior PVs than those of CC genotype. The findings suggest that rs2200733 may play a key role in regulating proper development and differentiation of atria/PVs.
Project description:The prediction of atrial fibrillation (AF) following catheter ablation of atrial flutter (Afl) would be helpful to facilitate targeted arrhythmia monitoring and anti-coagulation strategies. A single nucleotide polymorphism, rs2200733, is strongly associated with AF. We sought to characterize the association between rs2200733 and prevalent Afl and to determine if the variant could predict AF after cavotricuspid isthmus ablation.We performed a genetic association study of 295 patients with Afl and/or AF and 469 controls using multivariable logistic regression. The variant was then assessed as a predictor of incident AF after cavotricuspid isthmus ablation in 87 consecutive typical Afl patients with Cox proportional hazards models. The rs2200733 rare allele was associated with an adjusted 2.06-fold increased odds of isolated Afl (95% CI: 1.13-3.76, P = 0.019) and an adjusted 2.79-fold increased odds of a combined phenotype of AF and Afl (95% CI: 1.81-4.28, P < 0.001). Following catheter ablation for Afl, carrier status of rs2200733 failed to predict an increased risk of AF either among all subjects (adjusted HR: 0.94; 95% CI: 0.58-1.53, P = 0.806) or among those with isolated Afl (adjusted HR: 1.29; 95% CI: 0.51-3.26, P = 0.585).Our study demonstrates that Afl, whether occurring in isolation or along with AF, is associated with the rs2200733 AF risk allele. Genetic carrier status of rs2200733 failed to predict an increased risk of incident or recurrent AF following catheter ablation for Afl. These findings suggest that the causal mechanism associated with rs2200733 is germane to both AF and Afl.
Project description:Genome-wide association studies have identified numerous common polymorphisms associated with atrial fibrillation (AF). The 3 loci most strongly associated with AF occur at chromosome 4q25 (near PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3).To evaluate whether timing of AF recurrence after direct current cardioversion (DCCV) is modulated by common AF susceptibility alleles.A total of 208 patients (age 65 ± 11 years; 77% men) with persistent AF underwent successful DCCV and were prospectively evaluated at 3, 6, and 12 months for AF recurrence. Four single nucleotide polymorphisms--rs2200733 and rs10033464 at 4q25, rs7193343 in ZFHX3, and rs13376333 in KCNN3--were genotyped.The final study cohort consisted of 184 patients. In 162 (88%) patients, sinus rhythm was restored with DCCV, of which 108 (67%) had AF recurrence at a median of 60 (interquartile range 29-176) days. In multivariable analysis, the presence of any common single nucleotide polymorphism (rs2200733, rs10033464) at the 4q25 locus was an independent predictor of AF recurrence (hazard ratio 2.1; 95% confidence interval 1.21-3.30; P = .008). Furthermore, rs2200733 exhibited a graded allelic dose response for early AF recurrence (homozygous variants: 7 [interquartile range 4-56] days; heterozygous variants: 54 [28-135] days; and wild type: 64 [29-180] days; P = .03).To our knowledge, this is the first study to evaluate whether genomic markers can predict timing of AF recurrence in patients undergoing elective DCCV. Our findings show that a common polymorphism on chromosome 4q25 (rs2200733) is an independent predictor of AF recurrence after DCCV and point to a potential role of stratification by genotype.
Project description:Background:Catheter ablation is increasingly being performed worldwide for atrial fibrillation (AF). However, there are concerns of lower success rates and higher complications of AF ablations performed in low-volume centers. Thus, we sought to evaluate the safety and efficacy of AF catheter ablation in a low-volume center using contemporary technologies. Methods and results:71 consecutive patients (50 paroxysmal AF [pAF] vs 21 persistent AF) who underwent first catheter ablation were studied. Primary outcome was AF recurrence rate. Secondary outcomes included periprocedural complications, hospitalization for symptomatic tachy-arrhythmias post-ablation and number of repeat ablations. Mean age of our cohort was 59.1 ± 9.7 years, of which 56 (78.9%) were males. 1-year AF recurrence was 19.5% in pAF and 23.8% in persistent AF (p = 0.694). Ablation in persistent AF group required longer procedural (197.76 ± 48.60 min [pAF] vs 238.67 ± 70.50 min [persistent AF], p = 0.006) and ablation duration (35.08 ± 15.84 min [pAF] vs 52.65 ± 28.46 min [persistent AF], p = 0.001). There were no significant differences in secondary outcomes. Major periprocedural complication rate was 2.8%.Subset analysis on (i) cryoablation vs radiofrequency, (ii) Ensite vs CARTO navigational system and (iii) circular vs high density mapping catheter did not yield significant differences in primary or secondary outcomes. Conclusions:The AF ablation complication and recurrence free rates in both paroxysmal and persistent AF at one year were comparable to high-volume centers. Long-term follow up is needed. In addition, first AF catheter ablation in a low-volume center is realistic with comparable efficacy and safety outcomes to high-volume centers using contemporary ablation technologies.
Project description:Common single nucleotide polymorphisms at chromosome 4q25 (rs2200733, rs10033464) are associated with both lone and typical atrial fibrillation (AF). Risk alleles at 4q25 have recently been shown to predict recurrence of AF after ablation in a population of predominately lone AF, but lone AF represents only 5%-30% of AF cases.To test the hypothesis that 4q25 AF risk alleles can predict response to AF ablation in the majority of AF cases.Patients enrolled in the Vanderbilt AF Registry underwent 378 catheter-based AF ablations (median age 60 years; 71% men; 89% typical AF) between 2004 and 2011. The primary end point was time to recurrence of any nonsinus atrial tachyarrhythmia (atrial tachycardia, atrial flutter, or AF).Two-hundred atrial tachycardia, atrial flutter, or AF recurrences (53%) were observed. In multivariable analysis, the rs2200733 risk allele predicted a 24% shorter recurrence-free time (survival time ratio 0.76; 95% confidence interval [CI] 0.6-0.95; P = .016) compared with wild type. The heterozygous haplotype demonstrated a 21% shorter recurrence-free time (survival time ratio 0.79; 95% CI 0.62-0.99) and the homozygous risk allele carriers a 39% shorter recurrence-free time (survival time ratio 0.61; 95% CI 0.37-1.0; P = .037).Risk alleles at the 4q25 loci predict impaired clinical response to AF ablation in a population of patients with predominately typical AF. Our findings suggest that the rs2200733 polymorphism may hold promise as an objectively measured patient characteristic that can be used as a clinical tool for selecting patients for AF ablation.
Project description:BACKGROUND AND OBJECTIVES:The association of susceptibility loci for atrial fibrillation (AF) with AF recurrence after ablation has been reported, although with controversial results. In this prospective cohort analysis, we aimed to investigate whether a genetic risk score (GRS) can predict the rhythm outcomes after catheter ablation of AF. METHODS:We determined the association between 20 AF-susceptible single nucleotide polymorphisms (SNPs) and AF recurrence after catheter ablation in 746 patients (74% males; age, 59±11 years; 56% paroxysmal AF). A GRS was calculated by summing the unweighted numbers of risk alleles of selected SNPs. A Cox proportional hazard model was used to identify the association between the GRS and risk of AF recurrence after catheter ablation. RESULTS:AF recurrences after catheter ablation occurred in 168 (22.5%) subjects with a median follow-up of 23 months. The GRS was calculated using 5 SNPs (rs1448818, rs2200733, rs6843082, rs6838973 at chromosome 4q25 [PITX2] and rs2106261 at chromosome 16q22 [ZFHX3]), which showed modest associations with AF recurrence. The GRS was significantly associated with AF recurrence (hazard ratio [HR] per each score, 1.13; 95% confidence interval [CI], 1.03-1.24). Patients with intermediate (GRS 4-6) and high risks (GRS 7-10) showed HRs of 2.00 (95% CI, 0.99-4.04) and 2.66 (95% CI, 1.32-5.37), respectively, compared to patients with low risk (GRS 0-3). CONCLUSIONS:Our novel GRS using 5 AF-susceptible SNPs was strongly associated with AF recurrence after catheter ablation in Korean population, beyond clinical risk factors. Further efforts are warranted to construct a generalizable, robust genetic prediction model which can guide the optimal treatment strategies.