Genetic and Metabolic Determinants of Congenital Heart Defect Risk

先天性心脏病风险的遗传和代谢决定因素

• 批准号: 7863983
• 负责人: CHARLOTTE A HOBBS
• 金额: $ 1.42万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7863983
• 关键词: Affect; Alcohols; Antioxidants; Biochemical Genetics; Biological Markers; Candidate Disease Gene; Cardiology; Childhood; Clinical; Collection; Complex; Computational Biology; Congenital Abnormality; Congenital Heart Defects; Coupling; DNA; Data; Development; Environment; Enzymes; Etiology; Exhibits; Folate; Foundations; Frequencies; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genomics; Genotype; Glutathione Metabolism Pathway; Haplotypes; Homocysteine; Homocystine; International; Lead; Life Style; Live Birth; Measures; Metabolic; Morbidity - disease rate; Obesity; Outcome; Oxidative Stress; Participant; Pathway interactions; Phase; Plasma; Positioning Attribute; Pregnancy; Prevention; Prevention program; Prevention strategy; Primary Prevention; Public Health; Reactive Oxygen Species; Recording of previous events; Research Infrastructure; Research Personnel; Risk; Sampling; Smoking; Translational Research; Woman; Work; base; case control; design; fetal; gene environment interaction; gene interaction; genetic epidemiology; genetic profiling; genetic variant; lifestyle factors; metabolic abnormality assessment; mortality; multidisciplinary; oxidative damage; tool

DESCRIPTION (provided by applicant): Congenital heart defects (CHDs) are the most common birth defects affecting 8-10 of every 1,000 live births. Although CHDs are associated with significant morbidity and mortality their etiology is mostly unknown, and few primary prevention strategies exist. Approximately 85% of CHDs are nonsyndromic and result from a complex interplay between genetic, environmental, and metabolic influences. Based on our recent discovery that women with CHD-affected pregnancies exhibit alterations in homocysteine and glutathione metabolism, we hypothesize that CHDs are associated with maternal oxidative stress, due to pro-oxidant lifestyle factors and genetic variants that result in altered folate-homocysteine metabolism, and glutathione antioxidant defense capacity. We further hypothesize that the metabolic alterations will be associated with increased frequency of genetic polymorphisms that functionally affect homocysteine and glutathione metabolism. Using genotype data generated from Phase I and Phase II of the International HapMap Project, the investigators will select a highly informative set of haplotype tagging SNPs (htSNPs) in 61 candidate genes encoding for critical enzymes in the folate, homocysteine, and transsulfuration pathways. Selected htSNPs will be genotyped in a large collection of DNA samples from participants in the National Birth Defects Prevention Study. The investigators will determine the association between CHDs and maternal and fetal genetic variants of candidate genes. Independent and modifying effects of pro-oxidant lifestyle factors, including preconceptional maternal obesity, smoking and alcohol will be characterized. In parallel, we will establish whether maternal metabolites among women with CHD-affected pregnancies exhibit evidence of oxidative damage and increased vulnerability to oxidative stress. Coupling metabolic studies with the capacity for high throughput genotyping and powerful new statistical approaches affords an unprecedented opportunity to characterize metabolic, genetic and environmental causes of CHDs. The outcome of this project will be immediate and direct contributions to the understanding of genetic, environmental, and metabolic causes of CHDs and the necessary foundation for clinical and public health primary prevention programs. The convergence of a large-scale case-control infrastructure, advances in genomic tools, and leading multidisciplinary expertise promises to produce a preconception metabolic and genetic profile that can be the basis of a primary prevention program. Successful completion of the proposed studies will advance translational research targeting these costly and devastating birth defects.

描述(申请人提供)：先天性心脏病(CHD)是最常见的出生缺陷，每1000名活产儿中有8-10人受到影响。虽然CHD与显著的发病率和死亡率有关，但其病因大多未知，而且几乎没有初级预防策略存在。大约85%的CHD是非综合征性的，是遗传、环境和代谢影响之间复杂相互作用的结果。根据我们最近的发现，患有CHD的怀孕妇女表现出同型半胱氨酸和谷胱甘肽代谢的变化，我们假设CHD与母亲的氧化应激有关，这是由于促氧化生活方式因素和导致叶酸-同型半胱氨酸代谢改变的遗传变异以及谷胱甘肽抗氧化防御能力的结果。我们进一步假设代谢改变将与功能上影响同型半胱氨酸和谷胱甘肽代谢的基因多态频率增加有关。 利用国际血型图谱项目第一阶段和第二阶段产生的基因数据， 研究人员将在61个候选基因中选择一组信息丰富的单倍型标签SNPs(HtSNPs)，这些基因编码叶酸、同型半胱氨酸和硫化途径中的关键酶。选定的htSNPs将在来自国家出生缺陷预防研究参与者的大量DNA样本中进行基因分型。研究人员将确定CHD与候选基因的母体和胎儿遗传变异之间的关联。将描述促氧化生活方式因素的独立和修饰作用，包括先入为主的母体肥胖、吸烟和酒精。同时，我们将确定患有冠心病的孕妇的母体代谢产物是否显示出氧化损伤的证据，并增加了对氧化应激的易感性。将代谢研究与高通量基因分型能力和强大的新统计方法相结合，为表征冠心病的代谢、遗传和环境原因提供了前所未有的机会。该项目的成果将为了解先天性心脏病的遗传、环境和代谢原因以及为临床和公共卫生一级预防计划奠定必要的基础做出直接和直接的贡献。大规模病例对照基础设施、基因组工具的进步和领先的多学科专业知识的融合有望产生可作为初级预防计划基础的先入为主的新陈代谢和基因图谱。拟议研究的成功完成将推进针对这些代价高昂且具有破坏性的出生缺陷的转译研究。