In Silico Assessment of Genetic Variation in PITX2 Reveals the Molecular Mechanisms of Calcium-Mediated Cellular Triggered Activity in Atrial Fibrillation*

摘要

Genome-wide association studies have identified genetic variants including rs13143308T in the homeobox gene Pitx2 associated with atrial fibrillation (AF) populations. However, the molecular mechanisms leading to AF due to the rs13143308T variant are poorly understood. Therefore, this study aims to investigate the effects of this variant-induced alteration in calcium handling on properties of Ca²⁺-transients (CaT) and spontaneous calcium-release events (SCaEs). Based on recent experimental data on variants-induced alterations in ryanodine receptor channels (RyR) and sarcoplasmic reticulum (SR) calcium ATPase 2a (SERCA2a), we incorporated modifications to calcium handling into a previously published model of the human atrial cardiomyocyte with a spatial representation of calcium wave propagation. We identified that the rs13143308T variant has a higher incidence of spontaneous membrane depolarizations and amplitude of CaT than atrial myocytes without this variant. We showed a higher density of SCaEs and content of SR Ca²⁺ in atrial myocytes with the rs13143308T risk variant. Further computational analysis revealed that these calcium-mediated triggered activities were mainly linked to the gain of SERCA2a function but not the RyR2 dysfunction. Taken together, our model provides a powerful tool for assessing the impact of genetic variants in Pitx2, and these simulated results enhance our understanding of the molecular mechanisms underlying Pitx2-induced AF.