These results directly link transcriptional control of SERCA2 activity, depressed SR Ca<sup>2+</sup> sequestration, enhanced trans-sarcolemmal calcium fluxes, and AF, establishing a mechanism underlying the genetic basis for a Ca<sup>2+</sup>-dependent pathway for AF risk.
Here, we identify the 4q25 variant rs13143308T as a genetic risk marker for AF, specifically associated with excessive calcium release and spontaneous electrical activity linked to increased SERCA2 expression and RyR2 phosphorylation.
There was no difference in hemodynamic properties, RyR2 binding, or suppression of ATP2A2 in either cohort of patients with AF when compared to patients with normal sinus rhythm (NSR).
We identified a multitiered transcriptional network that linked seven previously defined AF risk loci: TBX5 directly activated PITX2, and TBX5 and PITX2 antagonistically regulated membrane effector genes Scn5a, Gja1, Ryr2, Dsp, and Atp2a2 In addition, reduced Tbx5 dose by adult-specific haploinsufficiency caused decreased target gene expression, myocardial automaticity, and AF inducibility, which were all rescued by Pitx2 haploinsufficiency in mice.
Our data indicate that cardiac gene expression alterations in peripheral blood cells of IDCM patients may reflect alterations in LV function, whereas the presence of AF may be associated with increased SERCA2 levels in these patients.