Single-Nucleotide Polymorphisms, PITX2 and Abnormal Electrical Activity in Atrial Fibrillation

Since single-nucleotide polymorphisms (SNPs) associated with increased risk of atrial fibrillation (AF) on chromosome 4q25 are located near the transcription factor PITX2, research has investigated relationships between SNPs, PITX2 activity and atrial function to improve risk stratification and identify new therapies. Although PITX2 levels are heterogeneous, most studies converge towards lower PITX2 levels in patients with AF, and a 4q25 SNP has been reported to reduce PITX2 expression. However, there are several SNPs at 4q25 that segregate independently, and patients carrying different SNPs respond differently to ablation therapy. On the other hand, atrial-specific deletion of Pitx2c mimics molecular and electrophysiological alterations observed in patients with AF. This includes microRNAs, signaling pathways, ion channels, calcium homeostasis, electrical remodeling, contraction and the response to pharmacological treatments. Moreover, mutations in the PITX2 homeodomain are associated with AF, PITX2 dysfunction or impaired calcium homeostasis. Interestingly, myocytes with the 4q25 risk allele rs13143308T display electrophysiological alterations similar to those reported in patients with AF or mice with heterozygous Pitx2c deletion. Moreover, carriers of rs13143308T respond poorly to ablation or antiarrhythmic drug therapy. Future research needs to establish how different 4q25 SNPs impact different PITX2 isoforms and the downstream regulation of atrial function.