Genetic basis for congenital heart defects

描述(由申请人提供)：与公共健康相关：先天性心脏病(CHD)是婴儿发病率和死亡率的主要原因。这项建议提出了一种独特的方法来确定先天性心脏病(CHD)的遗传基础，使用研究人群作为敏化战略的基础，以确定CHD的遗传和环境风险因素。目标和与NHLBI的相关性：患有唐氏综合症(DS)的个体患AVSD的风险增加2000倍。虽然21号染色体基因剂量的增加明显导致了这种风险，但房室缺失只发生在20%而不是100%的DS患者中(并且只有50%有任何心脏病)，这表明21三体本身不足以导致CHD。因此，更多的遗传变异和/或环境因素会影响这一结果。高危DS人群不仅可以用来研究剂量敏感的chr21基因在冠心病病因学中的作用，而且还可以作为一个独特的“敏感”人群，在普通人群中识别AVSD的危险因素。我们已经获得了超过120名患有DS和心脏病(DS+AVSD)的患者及其父母的DMA、细胞系、环境问卷信息和临床数据，以及更多没有心脏病(DS-CHD)的DS人群，这是针对这一问题进行的最大规模的研究。利用我们现有的基础设施，我们将把这个集合扩展到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合。我们将通过有针对性的关联研究和/或对患有DS+AVSD的个体和适当对照的重新测序来评估候选基因。在我们之前的工作中，一个候选基因和三体之间的相互作用已经被发现。候选突变将在小鼠身上重新产生，并与三体背景杂交；这些模型提供了进入所有发育阶段的所有组织的途径，并且可以通过基因操作，提供了对全面了解CHD病因和改善干预措施的初步研究至关重要的工具。我们的目标是建立研究群体，对AVSD进行全面分析，并查询这些群体中的候选修饰基因。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.通过对AVSD相关基因进行重新测序，识别罕见的易感变异。3.利用小鼠模型，检测整倍体和三体小鼠候选基因突变在心脏分裂中的作用。这种方法的结合将使我们能够识别所有CHD的易感基因，并提供一个系统来准确地确定通过发育观察到的缺陷的病因。这些系统在改善冠心病干预措施的初步研究中将是无价的。

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.