Functional Genomics of Atrial Fibrillation in Human Atria

人类心房心房颤动的功能基因组学

• 批准号: 8400791
• 负责人: John Barnard
• 金额: $ 68.93万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 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/8400791
• 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; 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

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. PUBLIC HEALTH RELEVANCE: Atrial fibrillation (AF), associated with aging, obesity, risk for stroke, heart failure and death, afflicts millions of Americans with an incidence that is projected to triple over the next several decades. AF susceptibility is heritable, but despite successful identification of genetic variants associated with AF, the links between these findings and how they cause AF remain unclear. The proposed studies aim to make these functional connections, which will facilitate identification of new targets for AF treatment and prevention.

描述（由申请人提供）：房颤（AF）增加了心力衰竭，中风和死亡的风险，并且已发现AF具有重要的遗传成分。基因组广泛的关联研究（GWAS）已经确定了与AF风险增加有关的许多单核苷酸多态性（SNP）。但是，它们促进AF的因果变异，相关基因和机制尚不清楚。为了增强我们对可遗传AF中涉及的致病基因的理解，我们建议评估GWAS中发现的SNP的影响，在感兴趣的目标组织中，人类左心房从心脏外科手术患者的1000多个人类手术组织中获得了人类左心房对梅尔纳，miRNA和相关蛋白的表达。具体目的是：1）确定AF表型如何改变人类心房转录组，以及2）识别和测试候选候选功能遗传变异，以改变心房转录表达。 AIM 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与基因转录本的AF表型关联，包括低表达的转录本和mRNA同工型，miRNA和miRNA，以及共同指导的基因模块。我们将使用siRNA敲低和cDNA转染策略在心房心肌细胞系，人ESC衍生的心房细胞以及人类心房成纤维细胞中测试调节所选基因的功能效应，以确定这些基因的表达是否改变了这些基因的表达是否影响下游基因表达和选定的生物学途径。 AIM 2研究将通过表达定量性状基因座（EQTL）和等位基因表达不平衡分析来鉴定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 对最近的GWAS的逻辑和重要随访，它将为高度与AF相关的SNP的影响提供新颖的，无偏见的机理见解。我们希望我们的研究能够确定与AF相关的遗传基因座和基因表达之间的功能联系，并鉴定与AF的病因和进展有因果关系的SNP，基因和途径，并且可能代表AF治疗和预防的新目标。 公共卫生相关性：与衰老，肥胖，中风，心力衰竭和死亡有关 在接下来的几十年中三倍。 AF易感性是可遗传的，但是尽管成功鉴定了与AF相关的遗传变异，但这些发现与它们引起AF的联系之间的联系仍然不清楚。拟议的研究旨在建立这些功能连接，这将有助于确定新目标用于AF治疗和预防。