The Genetic Basis of Conotruncal Defects

圆锥干缺陷的遗传基础

• 批准号: 8127848
• 负责人: Elizabeth Goldmuntz
• 金额: $ 75.46万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127848
• 关键词: Address; Anatomy; Arteries; Cardiac; Case Study; Childhood; Clinical; Clinical Data; Cohort Studies; Complex; Complex Genetic Trait; Congenital Abnormality; Congenital Heart Defects; DNA; Databases; Defect; Developmental Biology; Diagnosis; Disease; Environmental Risk Factor; Etiology; Family; Genes; Genetic; Genetic Variation; Genomics; Genotype; Health; Human Genome; Individual; Infant; Inherited; Institution; Instruction; Investigation; Life; Measures; Medical; Meta-Analysis; Methods; Morbidity - disease rate; Mutation; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Outcome; Parents; Pathway interactions; Phenotype; Prevention strategy; Prevention therapy; Preventive; Public Health; Recruitment Activity; Research; Research Design; Research Personnel; Resources; Risk; Risk Factors; Sampling; Single Nucleotide Polymorphism; Subgroup; Systems Analysis; Testing; Tetralogy of Fallot; Therapeutic; Triad Acrylic Resin; Variant; base; case control; cohort; design; disorder risk; follow-up; genetic risk factor; genetic variant; genome wide association study; genome-wide; insight; member; mortality; novel; trait

DESCRIPTION (provided by applicant): Despite remarkable medical and surgical advances, congenital heart defects (CHD) continue to be associated with significant morbidity and early mortality and present a substantial public health concern. However, the etiology of CHD is poorly understood and thus preventive strategies and therapies based on mechanism of disease are few. Evidence suggests that both genetic and environmental factors contribute to the etiology of CHD and it is increasingly apparent that CHD are complex genetic traits where the risk of disease is determined by the combination of multiple genetic factors. Research suggests that genetic factors influence clinical outcome as well. With rapid technological and methodological advances, large scale genomic analyses to identify genetic risk factors in common diseases characterized as complex traits are now possible but require large study cohorts. The establishment of the Pediatric Cardiac Genomics Consortium promises to overcome this last hurdle. This application proposes to perform genome wide studies in a large, related group of CHD, namely conotruncal defects, to identify genetic risk factors for disease. The association of genetic variants (single nucleotide polymorphisms and copy number variants) with the risk of disease will be tested in a discovery cohort, and findings replicated exactly in a replication cohort. Systems analyses to discover disease related pathways will also be performed. In conjunction with pre-existing samples, cases ascertained by the Consortium will allow for full-cohort and subgroup analyses defined by specific diagnoses. Analyses will be followed by deep sequencing of associated genes, CNVs and members of pathways to identify specific disease-related genetic alterations. Finally, analyses exploring the association of genotype with clinical outcome in the subset of cases with tetralogy of Fallot will be performed. The proposed studies provide a relatively unbiased approach to identify novel genetic risk factors for this large group of CHD. In conjunction with discoveries from the Developmental Biology Consortium, these studies will identify novel mechanisms of disease and begin to advance opportunities for the prevention and therapy of CHD and associated morbidities. RELEVANCE (See instructions): Congenital heart defects (CHD) are the most common, major birth defect and continue to be associated with significant life-long morbidities and early mortality. These studies will begin to identify genetic factors for a large subset of CHD whose etiology is otherwise poorly understood. Such discoveries will provide insight into the mechanisms of disease and allow for more strategic preventive and therapeutic health measures.

描述（由申请人提供）： 尽管医学和外科手术取得了显著进步，但先天性心脏病（CHD）仍然与显著的发病率和早期死亡率相关，并成为一个重大的公共卫生问题。然而，冠心病的病因学知之甚少，因此基于疾病机制的预防策略和治疗方法很少。有证据表明，遗传和环境因素都有助于CHD的病因，并且越来越明显的是，CHD是复杂的遗传特征，其中疾病的风险由多种遗传因素的组合决定。研究表明，遗传因素也会影响临床结果。随着技术和方法的快速进步，大规模的基因组分析，以确定复杂特征的常见疾病的遗传风险因素，现在是可能的，但需要大规模的研究队列。儿科心脏基因组学联盟的成立有望克服这最后一个障碍。本申请提出在一个大的相关CHD组中进行全基因组研究，即圆锥动脉干缺陷，以鉴定疾病的遗传风险因素。遗传变异（单核苷酸多态性和拷贝数变异）与疾病风险的关联将在发现队列中进行测试，并在复制队列中准确复制发现。还将进行系统分析，以发现疾病相关途径。联合会确定的病例与先前存在的样本一起，将允许进行由特定诊断定义的全队列和亚组分析。分析之后将对相关基因、CNV和途径成员进行深度测序，以确定特定疾病相关的遗传改变。最后，将进行分析，探讨基因型与法洛四联症病例亚组临床结局的相关性。拟议的研究提供了一个相对公正的方法来确定新的遗传危险因素，这一大组冠心病。结合发育生物学联盟的发现，这些研究将确定疾病的新机制，并开始推进CHD和相关疾病的预防和治疗机会。相关性（参见说明）：先天性心脏病（CHD）是最常见的，主要的出生缺陷，并继续与显着的终身发病率和早期死亡率。这些研究将开始以确定一个大的冠心病子集的遗传因素，其病因是否则知之甚少。这些发现将有助于深入了解疾病的机制，并允许采取更具战略性的预防和治疗保健措施。