New single nucleotide polymorphisms associated with supraventricular arrythmias in patients with pacemaker implantation: genome-wide association approach and pooled DNA strategy

Abstract

Aims: The objective of this study was to use genome-wide association approach and pooled DNA strategy to search for new genomic loci associated with inter-individual differences in patients with pacemakers placed for sinus node dysfunction in form of sick sinus syndrome (SSS) or tachycardia-bradycardia syndrome (TB) and/or atrio-ventricular (AV) conduction disturbances (AV blocks). Methods and results: Study cohort consisted of 619 patients (recruited from the areas of central Poland) with pacemaker placement and 66 control patients (no pacemaker implantation or history of atrial arrhythmias). We tested association of single nucleotide polymorphisms (SNPs) genotyped using high density microarray platform with 3 groups separated on the basis of the diagnosis associated with pacemaker implantation (AV n=233, SSS n=171, and TB n=215), followed by individual genotyping of most significant SNPs identified in the microarray genomic scan. From the number of 23 initially genotyped SNPs we identified SNP rs2200733 located in the proximity of the PITX2 gene, which showed statistically significant differences between controls (MAF=11%) and 3 pacemaker groups (TB 24.2%; SSS 13.3% and AV 17.4%). The highest statistical significance (p value of 0.005 for minor allele frequency difference in individual genotyping) was observed for SNP in the TB group and AV group (p=0.016) when compared with control. Conclusions: Previous genome-wide association studies implicated a region of human chromosome 4q25 in familial atrial fibrillation (AF) and atrial flutter (AFl), approximately 150 kb distal to the PITX2 homeobox gene, a developmental left-right asymmetry (LRA) gene. In this respect the observed difference in allelic frequency for the investigated PITX2 polymorphism may be associated with the etiology underlying pacemaker placement in the TB group which was, in contrast to SSS group, associated with the frequent episodes of underlying AF. The genome-wide approach might provide an opportunity to identify novel candidate genes and pathways related to the diagnosis of cardiac arrhythmias and indication for the pacemaker implantation. In addition, our findings implicate PITX2 and PITX2-mediated LRA-signaling pathways in prevention of atrial arrhythmias.