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: 8316456
• 负责人: Shamone Robinette Gore Panter
• 金额: $ 3.07万
• 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/8316456
• 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.

描述（由申请人提供）：与心房颤动相关基因座的遗传研究 心房颤动（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，它与死亡率和发病风险增加 2 倍以及中风风险增加 4 至 5 倍相关。房颤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房颤的发生中发挥作用。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。我们和其他人重复了这一发现。此外，我们是一个进行荟萃分析的联盟的成员，该分析已确定该 4q25 区域中与 AF 独立相关的 5 个 SNP。其中一个 SNP 位于距该区域最近的基因 PITX2 下游约 27 Kb。 PITX2 似乎是导致 AF 的基因的绝佳候选者，因为它是距离罪魁祸首 4q25 区域最近的基因，并且众所周知，它在心脏发育过程中的左/右不对称中起着重要作用。此外，Pitx2 +/- 小鼠在接受心脏电起搏时容易出现心律失常。 GWAS 发现染色体 9p21 上与冠状动脉疾病相关的 SNP 也位于基因间区域；并且，该区域已被证明具有增强子活性，影响距离超过 60 Kb 的最近基因的表达。因此，我们假设4q25区域可能存在长程增强子和/或沉默子，并且这些可能直接影响PITX2或其他邻近基因的基因表达。为了研究这一假设，将进行体外和体内实验来识别和测试 4q25 区域中的功能转录调控元件，以确定它们对 Pitx2 和邻近基因的基因表达的影响。