Genetic basis for congenital heart defects

先天性心脏病的遗传基础

• 批准号: 7201894
• 负责人: Roger H Reeves
• 金额: $ 118.31万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7201894
• 关键词: All Sites; Alleles; Animal Model; Biological Models; Birth; Candidate Disease Gene; Cell Line; Childhood; Chromosomes, Human, Pair 21; Clinical Data; Condition; Congenital Heart Defects; DNA Resequencing; Defect; Development; Down Syndrome; Environmental Risk Factor; Etiology; Family; Gene Dosage; Gene Mutation; Gene Targeting; General Population; Genes; Genetic; Genetic Variation; Goals; Health; Heart; Heart Diseases; Human; Incidence; Individual; Infant; Intervention; Lead; Linkage Disequilibrium; Live Birth; Localized; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Numbers; Organism; Outcome; Parents; Pathway interactions; Point Mutation; Population; Population Study; Predisposition; Public Health; Questionnaires; Rate; Recruitment Activity; Research Infrastructure; Research Personnel; Risk; Risk Factors; Role; Staging; Standards of Weights and Measures; Statistical Methods; Susceptibility Gene; System; Testing; Tissues; Trisomy; Variant; Work; atrioventricular septal defect; base; cardiogenesis; case control; dosage; genetic variant; genome wide association study; human population study; interdisciplinary approach; mortality; mouse model; tool

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.

描述（由申请人提供）： 与公众健康的相关性：先天性心脏病 (CHD) 是婴儿发病和死亡的主要原因。该提案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，利用研究人群作为识别先天性心脏病遗传和环境风险因素的敏化策略的基础。目标以及与 NHLBI 的相关性：唐氏综合症 (DS) 患者患 AVSD 的风险增加 2000 倍。虽然 21 号染色体基因剂量的增加显然会增加这种风险，但只有 20% 而不是 100% 的 DS 个体会发生 AVSD（并且只有 50% 的人患有心脏病），这表明 21 三体本身不足以引起 CHD。因此，额外的遗传变异和/或环境因素会影响这一结果。高风险 DS 人群不仅可用于研究剂量敏感的 chr21 基因在 CHD 病因学中的贡献，还可作为独特的“敏化”人群，在一般人群中识别 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) 的个体及其父母的 DMA、细胞系、环境问卷信息和临床数据，以及更多的不患有心脏病的 DS (DS - CHD) 人群，这是现有针对该问题的最大研究集。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。我们将通过有针对性的关联研究和/或在 DS + AVSD 个体和适当对照中进行重新测序来评估候选基因。我们之前的工作已经确定了一个候选基因与三体性之间的相互作用。候选突变将在小鼠中重新创建并与三体背景杂交；这些模型提供了对所有发育阶段的所有组织的访问，并且可以进行基因操作，为充分了解冠心病的病因以及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以全面分析 AVSD 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 相关基因进行重测序来识别罕见的易感性变异。 3. 使用小鼠模型测试整倍体和三体小鼠候选基因突变在心脏间隔中的作用。这种方法的结合将使我们能够识别所有先心病的易感基因，并提供一个系统来精确确定发育过程中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具有无价的价值。