Pitx2 Adjacent Noncoding RNA: A New, Long, Noncoding Kid on the 4q25 Block

Almost a decade ago, the deCODE (geCODE genetics Inc, Reykjavik, Iceland) consortium published the first genome-wide analysis of common gene variants associated with atrial fibrillation (AF). They found a gene variant on chromosome 4q25, ≈150 kB upstream of the PITX2 gene, to be the most important risk variant predisposing to AF.1 This initial observation has since been replicated and refined: We know of at least 6 independent single nucleotide variants, located at a 25 to 200 kB distance from the PITX2 gene, which modify the risk for AF.2 Furthermore, the risk allele of the initial variant is associated with recurrent AF in several clinical settings.

See Article by Gore-Panter et al

The initial observation has added a new dimension to our understanding of the mechanisms causing AF. Several research groups took this initial finding and studied the function of PITX2, a transcription factor with a known function in the development of heart and lungs, in the adult heart and specifically in the left atrium. Several important observations have been reported: PITX2c is expressed in the adult human and murine left atrium,3 whereas it is virtually absent in other parts of the adult heart. Genetic modifications that reduce left atrial PITX2 mRNA levels predispose mouse hearts to inducible AF.3–5 Reducing PITX2 levels alters the expression of several relevant left atrial genes,6 and the effects of PITX2 on gene regulation are partially mediated by the miR-17 to miR-92 complex.7 Preliminary analyses suggest that PITX2 …