Gene and Nutrient Etiologies of Human Heart Defects

描述（由申请人提供）：先天性心脏缺陷是人类出生缺陷中最常见的解剖类群，但对其病因知之甚少，圆锥体缺陷是先天性心脏缺陷的一个重要子集。预防圆锥体缺陷最有希望的线索之一是，在怀孕早期服用含有叶酸的维生素的妇女风险降低，这是该研究小组首次报道的一项发现。然而，叶酸有助于降低这些风险的潜在机制尚不清楚，激发我们研究的关键问题是，在围孕期服用叶酸补充剂的妇女中，有相当一部分人的后代可能患有这些心脏缺陷。本研究提出了一个广泛的心脏缺陷基因和危险因素发现计划，其目的是通过：1)研究与叶酸通路相关的20个新的遗传多态性；2)探索胆碱、维生素B12、蛋氨酸等重要营养因子的膳食摄入，控制叶酸的摄入；3)研究氧化应激的措施；4)比较有心脏缺陷的孕妇和没有心脏缺陷的孕妇在妊娠中期血清中的特定甲基供体营养素和抗体。这项多学科综合的5年研究计划将使用两个基于人群的流行病学数据集，其中包含550名患有圆锥锥体缺陷的婴儿或胎儿和1060名非畸形对照婴儿的数据，并结合最先进的实验室人类DNA基因分型方法和妊娠中期血清标本。该研究项目有四个合作机构，分别是加州出生缺陷监测项目、生物科学与技术研究所、德克萨斯农工大学、奈梅亨大学和奥克兰儿童医院研究所。这项研究利用了研究人员在分子和营养流行病学、临床和分子遗传学以及致畸学方面的集体专业知识。这项研究计划将加强对心脏缺陷的遗传和营养原因的科学认识。由于这些缺陷导致大量发病率以及高昂的情感和经济成本，因此进一步的科学理解导致可能的预防将极大地造福社会。

DESCRIPTION (provided by applicant): Congenital heart defects is the most common anatomical grouping of human birth defects, yet little is known about their etiologies, and conotruncal defects is an important subset of congenital heart defects. One of the most promising clues about preventing conotruncal defects is that women who use vitamins containing folic acid in early pregnancy are at reduced risk, a finding first reported by this research group. However, the underlying mechanisms by which folic acid contributes to these reduced risks are unknown, and the key issue that motivates our research is that a substantial proportion of women who take folic acid supplements in the periconceptional period nevertheless may deliver offspring affected with these heart defects. This research proposes an extensive heart defect gene and risk factor discovery program with aims that focus on etiologies of conotruncal defects by: 1) studying 20 new genetic polymorphisms related to the folate pathway; 2) exploring dietary intake of important nutritional factors such as choline, vitamin B12, and methionine, controlling for folate intake; 3) investigating measures of oxidative stress; and 4) measuring specific methyl-donor nutrients and antibodies in midpregnancy sera from women who deliver fetuses/infants with heart defects compared to those who do not. This multidisciplinary and integrated 5-year research program will use two large population-based epidemiologic datasets containing data on 550 infants or fetuses with conotruncal defects and 1060 nonmalformed control infants in combination with state-of-the-art laboratory genotyping methods of human DNA, and mid-pregnancy serum specimens. The research program has four collaborating institutions, the California Birth Defects Monitoring Program, the Institute of Biosciences and Technology, Texas A&M University, University of Nijmegen, and Children's Hospital Oakland Research Institute. The research capitalizes on the investigators' collective expertise in molecular and nutritional epidemiology, clinical and molecular genetics, and teratology. This research program will enhance scientific understanding of the genetic and nutritional causes of heart defect. Because these defects result in substantial morbidity as well as high emotional and economic costs, further scientific understanding leading to possible prevention would greatly benefit society.