Genetic Studies of Loci Associated with Atrial Fibrillation

与心房颤动相关基因座的遗传学研究

• 批准号: 8205145
• 负责人: Shamone Robinette Gore Panter
• 金额: $ 3.38万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8205145
• 关键词: 4q25; 9p21; Affect; Arrhythmia; Atrial Fibrillation; Binding; Bioinformatics; Biological Assay; Cardiac; Cardiac Myocytes; Chromosomes; Chromosomes, Human, Pair 3; Cloning; Coronary Arteriosclerosis; DNA; Data; Development; Diagnostic tests; Electrophoretic Mobility Shift Assay; Elements; Enhancers; Gene Expression; Genes; Genetic; Genetic Variation; Genome; Goals; Heart; Heart Atrium; Human; Human Genetics; In Vitro; Individual; Institutional Review Boards; Intercistronic Region; Knowledge; Left; Libraries; Maps; Measures; Meta-Analysis; Morbidity - disease rate; Mus; Mutation; Pathogenesis; Patients; Play; Postdoctoral Fellow; Predisposition; Protein Binding; Proteins; Protocols documentation; Publishing; Regulator Genes; Regulatory Element; Reporter Genes; Risk; Risk Factors; Role; Series; Shotguns; Site-Directed Mutagenesis; Stroke; Testing; Transfection; Variant; Viral; effective therapy; embryonic stem cell; gel mobility shift assay; genetic variant; genome wide association study; homologous recombination; human DNA sequencing; in vivo; mortality; mouse model; next generation; novel; research study; restriction enzyme; vector

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.

房颤（AF）的特征是心房颤动而不是协调收缩，是最常见的心律失常，它与死亡率和发病率增加2倍以及中风风险增加4至5倍有关。AF的许多危险因素已被确定，然而遗传成分的发现表明遗传变异可能在AF的发展中起作用。在已发表的全基因组关联研究（GWAS）中，在染色体4q25的基因间区域发现了AF易感位点。我们和其他人已经重复了这一发现。此外，我们参与了一项荟萃分析，确定了4q25区域中与AF独立相关的5个snp。其中一个snp位于该区域最接近的基因PITX2下游约27 Kb处。PITX2似乎是af致病基因的绝佳候选基因，因为它是最接近罪魁祸首4q25区域的基因，并且已知它在发育过程中心脏的左右不对称中起重要作用。此外，Pitx2 +/-小鼠在接受心脏电起搏时易发生心律失常。GWAS鉴定的与冠状动脉疾病相关的染色体9p21 SNP也位于基因间区；并且，该区域已被证明具有增强子活性，影响距离最近的超过60kb的基因的表达。因此，我们假设在4q25区域可能存在远程增强子和/或沉默子，这些可能直接影响PITX2或其他邻近基因的基因表达。为了验证这一假设，我们将在体外和体内进行实验，鉴定和测试4q25区域的功能性转录调控元件，确定它们对Pitx2及其邻近基因表达的影响。