Identification of Genetic and Molecular Mechanisms of Atrial Fibrillation

心房颤动的遗传和分子机制的鉴定

• 批准号: 8267035
• 负责人: Simon C Body
• 金额: $ 43.07万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267035
• 关键词: 4q25; Alternative Splicing; American; Amino Acid Sequence; Arrhythmia; Atrial Fibrillation; Biological; Candidate Disease Gene; Cardiac; Cardiac Surgery procedures; Caucasians; Caucasoid Race; Chinese People; Chromosomes; Chromosomes, Human, Pair 4; Code; Communities; Complementary DNA; DNA Resequencing; Development; Disease; Environment; Ethnic group; Functional RNA; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genetic Translation; Genetic Variation; Genomics; Genotype; Goals; Haplotypes; Heart Atrium; Heritability; Human; Individual; Maps; Measures; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Odds Ratio; Operative Surgical Procedures; Patients; Perioperative; Phenotype; Poly A; Poly(A)+ RNA; Population; Population Attributable Risks; Postoperative Period; RNA Splicing; Regulation; Risk; Role; Source; Stroke; Structure; Testing; Tissues; Transcript; Transcriptional Regulation; Translations; Variant; adverse outcome; aging population; cohort; cost; genetic variant; human disease; insight; lifetime risk; mortality; novel; novel therapeutics; public health relevance

DESCRIPTION (provided by applicant): Atrial fibrillation is the most frequent sustained arrhythmia with a lifetime risk of 20-24% and is a significant cause of stroke, and other morbidity and mortality. There is strong evidence for heritability of AF, with a frequent intergenic chromosome 4 locus (4q25) being recently associated with AF in ambulatory populations. We have recently demonstrated that the same SNPs in the 4q25 locus, are also associated with new-onset postoperative AF in replicated cohorts of Caucasian patients after cardiac surgery. Thus, the genetic mechanisms of ambulatory AF and postoperative AF appear to be aligned, however, the mechanism(s) have not yet been identified. We will use the perioperative cardiac surgical environment, with its availability of atrial tissue and frequent AF phenotype to determine the biological mechanism(s) of the association between 4q25 genomic variation and AF. Our overall goal is to identify the genetic and molecular mechanisms whereby genetic variation in the 4q25 locus causes atrial fibrillation. In order to achieve this goal, we propose examining hypotheses for the association of 4q25 variants with AF: 1) We hypothesize that 4q25 variant(s) cause altered primary protein structure responsible for increased risk of AF. In order to identify 4q25 variants that lie within known and novel coding sequences we will measure novel atrial poly-A transcripts using Solexa sequencing of cDNA tags. We will then genotype all polymorphic coding variants in over 1900 previously collected cardiac surgical patients to identify all 4q25 coding variation associated with postoperative AF; 2) We hypothesize that 4q25 variants cause alternative splicing or differential expression of cis mRNA transcripts. We will identify 4q25 transcripts that are either differentially expressed or alternatively spliced, depending upon 4q25 AF-associated genotype, by mapping the 4q25 poly-A transcriptome of the human atrium using a structured cohort of 40 patients with and without postoperative AF, and Solexa mRNA sequencing; 3) We hypothesize 4q25 variants cause AF by regulation of mRNA translation by miRNA or other non-coding RNA. We will perform studies to identify non-coding RNA sources of regulation of 4q25 mRNA translation by resequencing all identified atrial poly-A and non poly-A RNA transcripts within 4q25 in the same structured cohort of 40 patients with and without postoperative AF. We will integrate the findings from the transcript and sequencing efforts to test the hypothesis. By performing these studies we will provide new insights into the molecular mechanisms that initiate AF. These insights may facilitate the development of novel therapeutic strategies to alleviate the burden of AF in the community, notably in the aging population. PUBLIC HEALTH RELEVANCE: Atrial fibrillation is the most frequent sustained arrhythmia with a lifetime risk of 20-24% and is a significant cause of stroke, and other morbidity and mortality. An intergenic chromosome 4 locus has recently been associated with AF. We have demonstrated that the same 4q25 locus is also associated with new-onset postoperative AF after cardiac surgery. However the mechanisms underlying the association of the 4q25 locus and either ambulatory or postoperative AF has not yet been identified. We therefore propose to use the perioperative cardiac surgical environment, with its ready availability of atrial tissue and frequent AF phenotype to determine the biological mechanism(s) of the association between 4q25 genomic variation and AF.

说明(申请人提供)：房颤是最常见的持续性心律失常，终生风险为20%-24%，是中风和其他发病率和死亡率的重要原因。有强有力的证据表明房颤的遗传性，最近在流动人群中频繁的基因间隔性4号染色体座位(4q25)与房颤有关。我们最近已经证明，在高加索人心脏手术后的重复队列中，4q25基因的相同SNPs也与新发的术后房颤相关。因此，动态房颤和术后房颤的遗传机制似乎是一致的，然而，机制(S)尚未确定。我们将利用围术期心脏外科手术环境、可获得的心房组织和频繁的房颤表型来确定4q25基因组变异与房颤关联的生物学机制(S)。我们的总体目标是确定4q25基因座的遗传变异导致心房颤动的遗传和分子机制。为了实现这一目标，我们建议检验4q25变异与房颤关联的假说：1)我们假设4q25变异(S)导致初级蛋白质结构改变，导致房颤风险增加。为了识别位于已知和新的编码序列中的4q25变异体，我们将使用cDNA标签的Solexa测序来测量新的心房聚A转录本。然后，我们将对之前收集的1900多名心脏手术患者的所有多态编码变体进行分型，以确定所有与术后房颤相关的4q25编码变异；2)我们假设4q25变异导致顺式mRNA转录本的选择性剪接或差异表达。我们将通过使用40名术后有房颤和不有房颤的患者的结构化队列和Solexa mRNA测序来确定4q25转录本的差异表达或选择性剪接，这取决于4q25房颤相关的基因型；3)我们假设4q25变体是通过miRNA或其他非编码RNA调节mRNA翻译而导致房颤的。我们将对40名有和没有术后房颤的患者进行研究，通过对4q25内所有已识别的心房聚A和非聚A RNA转录本进行重新测序，以确定调控4q25 mRNA翻译的非编码RNA来源。我们将结合文字记录和测序工作的结果来检验这一假说。通过进行这些研究，我们将对引发房颤的分子机制提供新的见解。这些见解可能有助于开发新的治疗策略来减轻社区房颤的负担，特别是在老龄化人口中。 公共卫生相关性：房颤是最常见的持续性心律失常，终生风险为20%-24%，是中风和其他发病率和死亡率的重要原因。最近发现了一个与房颤相关的基因间隔性4号染色体。我们已经证明，同样的4q25基因座也与心脏手术后新发的房颤有关。然而，4q25基因座与动态或术后房颤的关联机制尚未确定。因此，我们建议利用围手术期心脏外科手术环境，利用其容易获得的心房组织和频繁的房颤表型来确定4q25基因组变异与房颤关联的生物学机制(S)。