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Genetic Studies of Loci Associated with Atrial Fibrillation

与心房颤动相关基因座的遗传学研究

基本信息

批准号：
8514700
负责人：
Shamone Robinette Gore Panter
金额：
$ 2.19万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2014-04-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8514700
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 deep sequencing 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

项目摘要

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）：房颤相关基因座的遗传学研究房颤（AF）的特征是心房收缩而不是协调收缩，是最常见的心律失常，与死亡率和发病率增加2倍以及中风风险增加4- 5倍相关。许多风险因素已被确定为AF，但遗传成分的发现表明，遗传变异可能在AF的发展中发挥作用。在已发表的全基因组关联研究（GWAS）中，已在染色体4 q25的基因间区域鉴定出AF易感性位点。我们和其他人已经复制了这一发现。此外，我们是一个联盟的一部分，该联盟进行了一项荟萃分析，确定了该4 q25区域中与AF独立相关的5个SNP。其中一个SNP位于PITX 2下游约27 Kb处，PITX 2是该区域最近的基因。PITX 2似乎是AF引起基因的一个很好的候选者，因为它是最接近罪魁祸首4 q25区域的基因，并且已知它在发育期间心脏的左/右不对称中很重要。此外，已经描述了Pitx 2 +/-小鼠，其在经受心脏电起搏时易患心律失常。GWAS鉴定的与染色体9 p21上的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影响超过60 Kb的最近基因表达的增强子活性。因此，我们假设在4 q25区域中可能存在长距离增强子和/或沉默子，并且这些增强子和/或沉默子可能直接影响PITX 2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以鉴定和测试4 q25区域中的功能性转录调控元件，确定它们对Pitx 2和邻近基因的基因表达的影响。