Genetic and Metabolic Determinants of Congenital Heart Defect Risk

描述（由申请人提供）：先天性心脏缺陷（CHDs）是最常见的出生缺陷，每1000个活产婴儿中有8-10个患有先天性心脏缺陷。虽然冠心病与显著的发病率和死亡率相关，但其病因尚不清楚，也很少有一级预防策略存在。大约85%的冠心病是非综合征性的，是遗传、环境和代谢影响复杂相互作用的结果。基于我们最近的发现，患有冠心病的孕妇表现出同型半胱氨酸和谷胱甘肽代谢的改变，我们假设冠心病与母亲氧化应激有关，由于促氧化的生活方式因素和基因变异导致叶酸-同型半胱氨酸代谢和谷胱甘肽抗氧化防御能力的改变。我们进一步假设，代谢改变将与基因多态性频率增加有关，这些多态性在功能上影响同型半胱氨酸和谷胱甘肽的代谢。

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.