By tissue culture, in vivo transgenics and analysis of chromatin structure, we have found that this region contains potentiator cis-regulatory elements that interact with the promoters of Pitx2c and, unexpectedly, Enpep, the next gene located downstream of Pitx2. Given the expression of Enpep in the sinoatrial node (SAN) and the co-expression of Pitx2 and Enpep in pro-arrhythmogenic regions of the embryonic heart, such as the sleeves of the pulmonary veins, our data suggest that de-regulation of these genes could underlie increased risk of AF. Here, PITX2 is linked to atrial fibrillation.