Pitx2 in atrial fibrillation

项目摘要： Pitx 2同源结构域转录因子是左右不对称的中心转录调节因子， 在心脏内起控制心脏形态发生的作用。现在很明显，Pitx 2从根本上是 与AF有关，尽管这种联系的基础仍然模糊。Pitx 2-AF的第一个证据 在一项全基因组关联研究（GWAS）中发现， 早发型家族性AF。Pitx 2是最接近疾病相关单核苷酸的基因， 多态性（SNP）。4 q25 SNP的AF患者没有高血压、糖尿病和瓣膜缺陷。 此外，携带4 q25 SNP的患者更容易发生心源性卒中，这进一步增加了获得的紧迫性。 深入了解与4 q25 SNP相关的潜在分子机制。我们是第一个 报告称，Pitx 2杂合小鼠容易患AF，这表明Pitx 2水平降低会导致AF。 三个不同的小组随后复制了我们的发现。由于其在AF中的关键作用，我们 假设Pitx 2转录靶基因全基因组分析将提供新的 对Pitx 2 happloinsufficient状态下AF的分子机制具有根本性的重要见解。我们 初步的多组学分析表明，Pitx 2直接结合到一些基因，这些基因已经被 与AF有关的基因以及对活性氧类反应并诱导炎症的基因。 对房颤的遗传机制了解甚少。新的遗传学见解将是至关重要的， 诊断测试和家庭咨询。此外，对AF遗传学的深入了解将 随着人类基因组测序变得越来越多， 平凡最后，长期目标是开发基于固体的新的治疗策略。 这些科学信息将来自模式生物和人类遗传学的研究。

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.