Genetic and Metabolic Determinants of Congenital Heart Defect Risk

描述（由申请人提供）：先天性心脏缺陷（CHD）是最常见的出生缺陷，影响每1,000例活产婴儿中的8-10例。虽然CHD与显著的发病率和死亡率相关，但其病因大多未知，并且存在很少的一级预防策略。大约85%的冠心病是非综合征性的，是遗传、环境和代谢影响之间复杂相互作用的结果。基于我们最近的发现，患有CHD的孕妇表现出同型半胱氨酸和谷胱甘肽代谢的改变，我们假设CHD与母体氧化应激有关，这是由于促氧化生活方式因素和遗传变异导致叶酸-同型半胱氨酸代谢和谷胱甘肽抗氧化防御能力改变。我们进一步假设，代谢改变将与基因多态性的频率增加，在功能上影响同型半胱氨酸和谷胱甘肽代谢。 使用国际人类基因组单体型图项目第一和第二阶段的基因型数据， 研究人员将在61个候选基因中选择一组信息量很大的单倍型标记SNP（htSNP），这些基因编码叶酸、同型半胱氨酸和转硫途径中的关键酶。选择的htSNPs将在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。独立和修改影响的促氧化生活方式的因素，包括孕前母亲肥胖，吸烟和饮酒的特点。与此同时，我们将确定CHD影响的妊娠妇女中的母体代谢物是否表现出氧化损伤和对氧化应激的脆弱性增加的证据。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CHD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CHD的遗传、环境和代谢原因以及临床和公共卫生一级预防计划的必要基础做出直接贡献。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一个可以作为一级预防计划基础的孕前代谢和遗传特征。成功完成拟议的研究将推进针对这些昂贵和毁灭性的出生缺陷的转化研究。

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.