Genetic basis for congenital heart defects

描述（由申请人提供）：与公共卫生相关：先天性心脏缺陷（CHD）是婴儿发病和死亡的主要原因。本研究提出了一种独特的方法来确定先天性心脏缺陷（CHD）的遗传基础，使用研究人群作为敏感化策略的基础，以确定CHD的遗传和环境风险因素。目的及其与NHLBI的相关性：唐氏综合征（DS）患者发生AVSD的风险增加2000倍。虽然21号染色体基因的增加明显增加了这种风险，但AVSD只发生在20%而不是100%的DS个体中（只有50%患有任何心脏病），这表明21三体本身并不足以导致冠心病。因此，额外的遗传变异和/或环境因素会影响这一结果。DS高危人群不仅可以用于研究剂量敏感型chr21基因在冠心病病因学中的作用，还可以作为一种独特的“敏感”人群，用于识别普通人群中AVSD的危险因素。我们已经获得了120多名DS合并心脏病患者（DS + AVSD）及其父母的DMA、细胞系、环境调查问卷信息和临床数据，以及更大的无心脏病DS人群（DS - CHD），这是目前针对这一问题最大的研究。利用我们现有的基础设施，我们将扩展到600个DS + AVSD家族，为全基因组关联研究提供足够的基线研究集。我们将通过有针对性的关联研究和/或在DS + AVSD患者和适当对照中进行重测序来评估候选基因。在我们之前的工作中已经确定了一个候选基因与三体之间的相互作用。候选突变将在小鼠中重建，并交叉到三体背景；这些模型提供了进入所有发育阶段的所有组织的途径，并且可以进行遗传操作，为充分了解冠心病的病因和改善干预措施的初步研究提供了必不可少的工具。我们的目标是建立研究群体，对AVSD进行综合分析，并在这些群体中查询候选修饰基因。我们将：1；对候选基因进行关联研究，以确定导致冠心病易感性的常见变异；2. 通过重测序avsd相关基因鉴定罕见易感变异。3. 使用小鼠模型测试候选基因突变在整倍体和三体小鼠心脏分离中的作用。这种方法的结合将使我们能够识别所有冠心病的易感基因，并提供一个系统来精确地建立通过发育观察到的缺陷的病因。这些系统对于改善冠心病干预措施的初步研究将是无价的。

DESCRIPTION (provided by applicant): RELEVANCE TO PUBLIC HEALTH: Congenital heart defects (CHD) are the leading cause of morbidity and mortality in infants. This proposal presents a unique approach to identifying the genetic basis of congenital heart defects (CHD) using a study population as the basis of a sensitization strategy to identify genetic and environmental risk factors for CHD. GOALS AND RELEVANCE TO NHLBI: Individuals with Down syndrome (DS) have a 2000-fold increased risk of AVSD. While increased dosage of chromosome 21 genes clearly contributes to this risk, AVSD occurs in only 20% and not 100% of DS individuals (and only 50% have any heart disease), demonstrating that trisomy 21 itself is not sufficient to cause CHD. Thus additional genetic variation and/or environmental factors influence this outcome. The high risk DS population can be used not only to study the contributions of dosage-sensitive chr21 genes in the etiology of CHD, but also serves as a unique "sensitized" population in which to identify risk factors for AVSD in the general population. We have already acquired DMA, cell lines, environmental questionnaire information and clinical data for more than 120 individuals with DS and heart disease (DS + AVSD) and their parents, plus a larger population of DS without heart disease (DS - CHD), the largest study set for this problem in existence. Using our existing infrastructure, we will expand this set to 600 DS + AVSD families to provide an adequate baseline study set for a genome-wide association study. We will assess candidate genes by targeted association studies and/or by resequencing in individuals with DS + AVSD and in appropriate controls. An interaction between one candidate gene and trisomy has already been identified in our previous work. Candidate mutations will be recreated in mouse and crossed to a trisomic background; these models provide access to all tissues at all developmental stages and can be manipulated genetically, providing tools that are essential to a full understanding of the etiology of CHD, and for initial studies of ameliorative interventions. Our goals are to establish study populations for a comprehensive analysis of AVSD and query candidate modifier genes in these populations. We will: 1. Conduct association studies on candidate genes to identify common variants that lead to CHD susceptibility; 2. Identify rare susceptibility variants by resequencing AVSD-associated genes. 3. Use mouse models to test the roles in heart septation of candidate gene mutations in euploid and trisomic mice. This combination of approaches will allow us to identify susceptibility genes for all CHD and provide a system to establish precisely the etiology of defects observed through development. These systems will be invaluable in initial studies of ameliorative of interventions in CHD.