Genetic Studies of Loci Associated with Atrial Fibrillation

说明(申请人提供)：与房颤相关的基因座研究房颤(房颤)是最常见的心律失常，其特征是心房颤动而不是协调收缩，它与死亡率和发病率增加2倍的风险以及中风的风险增加4-5倍有关。房颤的危险因素很多，但可遗传成分的发现提示，遗传变异可能在房颤的发生发展中起作用。在已发表的全基因组关联研究中，在染色体4q25的一个基因间隔区发现了一个房颤易感基因。我们和其他人重复了这一发现。此外，我们是执行荟萃分析的财团的一部分，该财团在这个4q25区域发现了五个与房颤独立相关的SNP。其中一个SNPs位于PITX2下游约27kb处，PITX2是该区域的邻近基因。PITX2似乎是导致房颤的最佳候选基因，因为它是最接近罪魁祸首4q25区域的基因，而且众所周知，它在心脏发育过程中左右不对称的过程中起着重要作用。此外，Pitx2+/-小鼠被描述为在接受心脏电起搏时容易发生心律失常。在染色体9p21上发现的与冠状动脉疾病相关的单核苷酸多态(SNP)也位于基因间隔区；并且，该区域已被证明具有增强子活性，影响距离超过60kb的最近基因的表达。因此，我们推测在4q25区域可能存在长程增强子和/或抑制子，这些可能直接影响PITX2或其他邻近基因的基因表达。为了验证这一假说，将进行体外和体内实验，以确定和测试4q25区域的功能转录调控元件，以确定它们对Pitx2及其邻近基因的基因表达的影响。 公共卫生相关性：该项目的目标是确定与心房颤动相关的功能性遗传变异，从而扩大关于增加发生心房颤动风险的基因变化及其机制的现有知识。从这些研究中获得的信息可能有助于开发新的有效的房颤治疗方法、诊断测试和预防措施。

DESCRIPTION (provided by applicant): Genetic Studies of Loci Associated with Atrial Fibrillation Atrial fibrillation (AF), which is characterized as the quivering of the atria instead of coordinated contraction, is the most common cardiac arrhythmia, and it is associated with a 2- fold increased risk of mortality and morbidity and a 4- to 5- fold increased risk for stroke. Many risk factors have been identified for AF, however the discovery of heritable components suggests that genetic variation may play a role in AF development. In published genome-wide association studies (GWAS), an AF susceptibility locus has been identified in an intergenic region of chromosome 4q25. We and others have replicated this finding. Additionally, we are part of a consortium that has performed a meta-analysis that has identified five SNPs in this 4q25 region that are independently associated with AF. One of these SNPs is just ~27 Kb downstream from PITX2, the closet gene to this region. PITX2 appears to be an excellent candidate for an AF-causing gene as it is the closest gene to the culprit 4q25 region, and it's known to be important in left/right asymmetry of the heart during development. In addition, Pitx2 +/- mice have been described which are susceptible to arrhythmias when subjected to cardiac electrical pacing. A GWAS identified SNP associated with coronary artery disease on chromosome 9p21 is also located in an intergenic region; and, this region has been shown to have enhancer activity affecting the expression of the nearest genes that are more than 60 Kb away. Thus, we hypothesize that there may be long range enhancers and/or silencers in the 4q25 region and that these may directly affect gene expression of PITX2 or other neighboring genes. To investigate this hypothesis, in vitro and in vivo experiments will be performed to identify and test functional transcriptional regulatory elements in the 4q25 region determine their effects on gene expression of Pitx2 and neighboring genes. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify functional genetic variants associated with atrial fibrillation and thus expand the existing knowledge regarding the genetic changes and their mechanisms that increase ones risk for developing atrial fibrillation. The information gained in these studies may be useful the development of novel and effective treatments, diagnostic tests, and preventative measures for atrial fibrillation.