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学分组，但对其病因知之甚少，圆锥动脉干缺陷是先天性心脏缺陷的重要子集。关于预防圆锥动脉干缺陷的最有希望的线索之一是，在怀孕早期使用含叶酸维生素的妇女风险降低，这是该研究小组首次报告的发现。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，在围受孕期服用叶酸补充剂的相当大比例的女性可能会产生受这些心脏缺陷影响的后代。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，其目的是通过以下方式关注圆锥动脉干缺陷的病因：1）研究20个与叶酸途径相关的新的遗传多态性; 2）探索重要营养因子如胆碱、维生素B12和蛋氨酸的膳食摄入，控制叶酸摄入; 3）研究氧化应激的措施;和4）测量来自分娩有心脏缺陷的胎儿/婴儿的妇女与没有心脏缺陷的妇女的孕中期血清中的特异性甲基供体营养素和抗体。这项多学科和综合性的5年研究计划将使用两个大型的基于人群的流行病学数据集，其中包含550名圆锥动脉干缺陷婴儿或胎儿和1060名非畸形对照婴儿的数据，并结合最先进的人类DNA实验室基因分型方法和中期妊娠血清标本。该研究计划有四个合作机构，加州出生缺陷监测计划，生物科学和技术研究所，得克萨斯A & M大学，奈梅亨大学和儿童医院奥克兰研究所。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畸形学方面的集体专业知识。该研究计划将增强对心脏缺陷的遗传和营养原因的科学了解。由于这些缺陷会导致大量的发病率以及高昂的情感和经济成本，因此进一步的科学认识将导致可能的预防，这将极大地造福于社会。

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.