Pitx2 in atrial fibrillation

项目总结： Pitx2同源结构域转录因子是左右不对称中的中心转录调节因子， 心脏内控制心脏形态发生的功能。现在很明显，Pitx2从根本上说是 连接到AF，尽管这种连接的基础仍然不清楚。PITX2-AF的第一个证据 LINK是在一项基因组广泛关联研究(GWAS)中提出的，该研究涉及到染色体4q25的一个区域 早发性家族性房颤。Pitx2是与疾病相关的单核苷酸最接近的基因。 多态(SNP)。携带4q25SNP的房颤患者无高血压、糖尿病和瓣膜缺陷。 此外，携带4q25SNP的患者更容易发生心源性中风，进一步增加了获得 洞察与4q25单核苷酸多态性相关的潜在分子机制。我们是第一个 有报道称，Pitx2杂合子小鼠易发生房颤，表明Pitx2水平降低会导致房颤。 三个不同的小组随后重复了我们的发现。由于它在房颤中的关键作用，我们 假设对Pitx2转录靶基因的全基因组分析将提供新的和 对PITX2单倍体不足状态下房颤的分子机制的洞察至关重要。我们的 初步的多组学分析表明，Pitx2直接与一些已经被 与房颤有关，也与对活性氧物种有反应并引发炎症的基因有关。 目前对房颤的遗传机制了解甚少。新的基因洞察力将对 在未来的诊断测试和家庭咨询方面。此外，深入了解房颤的遗传学知识将 随着人类基因组测序变得越来越多，为患者管理提供关键资源 司空见惯。最后，长期目标是开发以固体为基础的新治疗策略 科学信息将来自于模型生物和人类遗传学的工作。

Project Summary: The Pitx2 homeodomain transcription factor is a central transcriptional regulator in left right asymmetry that functions within the heart to control cardiac morphogenesis. It is now clear that Pitx2 is fundamentally connected to AF although the basis for this connection remains obscure. The first evidence for the Pitx2-AF link was made in a Genome Wide Association Study (GWAS) implicating a region of chromosome 4q25 in early onset familial AF. Pitx2 was the gene in closest proximity to the disease associated single nucleotide polymorphism (SNP). AF patients with the 4q25 SNP were free of hypertension, diabetes and valve defects. Moreover, patients with the 4q25 SNP were more prone to cardioembolic stroke adding further urgency to gain insight to the underlying molecular mechanisms associated with the 4q25 SNP. We were the first group to report that Pitx2 heterozygous mice were predisposed to AF indicating that reduced levels of Pitx2 led to AF. Three different groups have subsequently replicated our findings. Because of its critical role in AF, we hypothesized that genome wide analysis of Pitx2 transcriptional target genes would provide novel and fundamentally important insight into the molecular mechanisms for AF in the Pitx2 happloinsufficient state. Our preliminary Multi-Omics analysis indicates that Pitx2 directly binds to a number of genes that have been implicated in AF and also genes that respond to reactive oxygen species and induce inflammation. There is poor understanding of the genetic mechanisms underlying AF. New genetic insights will be critical for diagnostic testing and family counseling in the future. Moreover, an in depth knowledge of genetics of AF will provide critical resources for patient management as human genome sequencing becomes more commonplace. Finally, there is the long term goal to develop novel therapeutic strategies based on solid scientific information that will come from work in model organisms and human genetics.