Novel association of polymorphic genetic variants with predictors of outcome of catheter ablation in atrial fibrillation: new directions from a prospective study (DECAF)

Abstract

Non-pulmonary vein (non-PV) triggers and left atrial (LA) scars perpetuate atrial fibrillation (AF) and limit the success rate of catheter ablation. In order to understand the genetic basis of these risk factors, we examined the association of selected single nucleotide polymorphisms (SNPs) with scar and non-PV triggers. Four hundred AF patients (67 %male, 62±12 years, LA size 45.3±7 mm, 64%non-paroxysmal) undergoing catheter ablation were prospectively enrolled. DNA extractions for16 AF-related SNPS from blood samples were performed of which 371 DNA samples were available for genotyping. Multivariate logistic regression analysis was used for assessing predictive role of individual SNP, and logistic kernel-machine approach was applied to test the cumulative effect of multiple SNPs as a group with non-PV triggers and LA scar. False discovery rate (FDR) was computed for all candidate SNPs to address multiple testing. SNPs rs6599230 and rs6843082 were inversely associated (OR 0.68, p=0.04, and 0.62, p=0.01, respectively) whereas rs1448817 (OR 1.74, p=0.04) and rs7193343 (OR 1.66, p=0.02) predicted higher risk of non-PV triggers. Genotypes for rs6599230 and rs6843082 conferred 51 % reduction in the odds for non-PV triggers (combined OR 0.49, p=0.019), while rs1448817 and rs7193343 demonstrated a combined OR of 1.93, p=0.025. FDR was controlled at 16 % to adjust for multiple testing. For LA scar, inverse association was observed with rs1448817 (OR 0.29, p=0.006), rs17042171 (OR 0.27, p=0.032), rs3807989 (OR 0.54, p=0.017), and rs6843082 (OR 0.56, p=0.009). Two SNPs were associated with increased scar risk: rs17375901 (OR 3.68, p=0.03) and rs7193343 (OR 1.74, p=0.037). For global association of SNPs with left atrial scar FDR was controlled at ≤10 % to adjust for multiple testing. This study has a strong clinical significance as it provides important insights into the molecular basis of pertinent therapeutic targets. Our findings demonstrate that the presence of certain genetic polymorphisms increases the risk of scar and non-PV triggers in AF patients. Therefore, PVAI alone will not be enough to eliminate the arrhythmia and the operators may need to identify and isolate the non-PV foci to maximize procedural success in patients carrying these risk variants. Clinical trial registration clinicaltrials.gov (NCT01751607).