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.