Functional Genomics of Atrial Fibrillation in Human Atria

人类心房心房颤动的功能基因组学

基本信息

批准号：
8504548
负责人：
John Barnard
金额：
$ 67.07万
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：
2012
资助国家：
美国
起止时间：
2012-07-03 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8504548
关键词：
4q25 Ablation Affect Aging Alleles American Atrial Fibrillation Bioinformatics Biological Biological Assay Cardiac Myocytes Cardiac Surgery procedures Cell Culture Techniques Cell Line Cells Cessation of life Chromosomes Clinical Complementary DNA Confounding Factors (Epidemiology)DNA Resequencing DNA Sequence Data Disease Distal Etiology Fibroblasts Finding by Cause Functional disorder Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genetic Variation Genomics Genotype Heart Heart Atrium Heart failure Human Incidence Intercistronic Region Interdisciplinary Study Lasers Left atrial structure Link Messenger RNA MicroRNAs Molecular Profiling Morphogenesis Muscle Cells Pathway interactions Patients Pattern Phenotype Predisposition Prevention Prevention therapy Protein Isoforms Proteins Pulmonary veins Quantitative Trait Loci RNA Sequences RNA Splicing Regulation Regulatory Element Reporter Genes Resources Risk Sampling Single Nucleotide Polymorphism Site Small Interfering RNA Stroke Technology Testing Tissues Transcript Transfection Validation Variant Weight base biobank candidate selection case control follow-up functional genomics gene function genetic variant genome wide association study genome-wide human embryonic stem cell human embryonic stem cell line innovation insight interest knock-down mRNA Stability next generation novel obesity risk transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) increases risk of heart failure, stroke and death, and AF has been found to have a significant heritable component. Genome wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with increased risk of AF. However, the causative variants, relevant genes and mechanisms by which they promote AF remain unclear. To enhance our understanding of the causative genes involved in heritable AF, we propose to evaluate the impact of SNPs identified in recent GWAS on the expression of messenger RNA, miRNA and related proteins in the target tissue of interest, human left atria, taken from a unique biorepository of over 1000 human atrial tissues from cardiac surgery patients. Specific aims are: 1) To determine how AF phenotypes alter the human atrial transcriptome, and 2) To identify and test candidate functional genetic variants that alter atrial transcript expression. Aim 1 studies will use state-of-the-art technology (RNA-seq, miRNA-seq) and bioinformatics to determine AF phenotype associations with gene transcripts, including lowly expressed transcripts and mRNA isoforms, and miRNAs, and co-regulated gene modules. We will test the functional effects of regulating selected genes using siRNA knockdown and cDNA transfection strategies in an atrial myocyte cell line, human ESC-derived atrial cells and in human atrial fibroblasts to determine whether altered expression of these genes affects downstream gene expression and selected biological pathways. Aim 2 studies will identify genetic variants associated with atrial gene expression by expression quantitative trait locus (eQTL), and allelic expression imbalance analyses. Candidate variants will be validated in reporter gene transfection studies. The proposed interdisciplinary studies are a logical and important follow up to recent GWAS that will provide novel, unbiased mechanistic insights into the impact of SNPs highly associated with AF on atrial RNA expression patterns. We expect our studies to identify functional links between AF-associated genetic loci and gene expression, and to identify SNPs, genes, and pathways that are causally related to the etiology and progression of AF and that may represent new targets for AF treatment and prevention.

描述（由申请人提供）：心房颤动 (AF) 会增加心力衰竭、中风和死亡的风险，并且已发现 AF 具有显着的遗传因素。全基因组关联研究 (GWAS) 已发现许多与 AF 风险增加相关的单核苷酸多态性 (SNP)。然而，它们促进房颤的致病变异、相关基因和机制仍不清楚。为了增强我们对遗传性房颤致病基因的理解，我们建议评估最近 GWAS 中鉴定的 SNP 对感兴趣的目标组织（取自人类左心房）中信使 RNA、miRNA 和相关蛋白表达的影响。独特的生物储存库，包含来自心脏手术患者的 1000 多个人体心房组织。具体目标是：1) 确定 AF 表型如何改变人类心房转录组，2) 识别和测试改变心房转录表达的候选功能遗传变异。目标 1 研究将使用最先进的技术（RNA-seq、miRNA-seq）和生物信息学来确定 AF 表型与基因转录本的关联，包括低表达转录本和 mRNA 亚型、miRNA 以及共同调控的基因模块。我们将在心房肌细胞系、人 ESC 衍生的心房细胞和人心房成纤维细胞中测试使用 siRNA 敲低和 cDNA 转染策略调节选定基因的功能效果，以确定这些基因的表达改变是否会影响下游基因表达和选定的生物途径。目标 2 研究将通过表达数量性状基因座 (eQTL) 和等位基因表达失衡分析来识别与心房基因表达相关的遗传变异。候选变体将在报告基因转染研究中得到验证。拟议的跨学科研究是这是最近 GWAS 的合理且重要的后续行动，将为与 AF 高度相关的 SNP 对心房 RNA 表达模式的影响提供新颖、公正的机制见解。我们希望我们的研究能够确定 AF 相关基因位点和基因表达之间的功能联系，并确定与 AF 病因和进展有因果关系的 SNP、基因和通路，并可能代表 AF 治疗和预防的新目标。