This research program will investigate nutritional and genetic risk factors for conotruncal heart defects. Conotruncal defects are complex human congenital anomalies whose etiologies are largely unknown. The research capitalizes on the investigators' collective expertise in molecular epidemiology, nutritional epidemiology, clinical and molecular genetics, and teratogenesis. The research program's three aims will focus on the etiologies of conotruncal defects by: 1) studying genetic variation of five genes related to folate metabolic pathways (5,10-methyltetrahydrofolate reductase, betaine homocysteine methyltransferases 1&2, N-acetyltransferase 1, and thymidylate synthase); 2) studying genetic variation of two folate transporters, folate receptor-alpha and reduced folate carrier; and 3) searching for genetic variation among nine candidate genes involved in development of the anterior heart field of the early embryo (NKX2-5, GATA4, GATA5, GATA6, ZFPM2, FOXH1, MEF2C, ISL1 and FGF8). The research program has two collaborating institutions, Children's Hospital Oakland Research Institute and the California Birth Defects Monitoring Program. This integrated 5-year research program will use a newly completed California population-based case-control study composed of 360 infants with conotruncal defects and 650 non-malformed control infants, delivered between 1999 and 2004. It will combine extensive epidemiological information from maternal interviews and nutritional surveys with maternal and infant genotyping, haplotyping, and mutation analysis. This is the largest case-control study of infants with conotruncal defects and will uniquely generate population-based genotypic data on folate-related genes and a broad survey of candidate genes encoding transcription factors that direct the differentiation of anterior heart field progenitors into myocytes of the right ventricle and outflow tract. Overall, this research program attempts to enhance our scientific understanding of the genetic and nutritional causes of conotruncal defects. If risk factors are identified by the study, there will be a potential for prevention of these heart defects in the future. Because conotruncal defects result in substantial morbidity, as well as high emotional and economic costs, expanding our understanding of their causes may lead to preventive interventions that would greatly benefit public health and society.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Ershow, Abby
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Children's Hospital & Res Ctr at Oakland
United States
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Osoegawa, Kazutoyo; Iovannisci, David M; Lin, Bin et al. (2014) Identification of novel candidate gene loci and increased sex chromosome aneuploidy among infants with conotruncal heart defects. Am J Med Genet A 164A:397-406
Shaw, Gary M; Yang, Wei; Carmichael, Suzan L et al. (2014) One-carbon metabolite levels in mid-pregnancy and risks of conotruncal heart defects. Birth Defects Res A Clin Mol Teratol 100:107-15
Zhu, Huiping; Yang, Wei; Shaw, Nathan et al. (2012) Thymidylate synthase polymorphisms and risk of conotruncal heart defects. Am J Med Genet A 158A:2194-203
Shaw, Gary M; Carmichael, Suzan L; Yang, Wei et al. (2010) Periconceptional nutrient intakes and risks of conotruncal heart defects. Birth Defects Res A Clin Mol Teratol 88:144-51
Kuehl, Karen; Loffredo, Christopher; Lammer, Edward J et al. (2010) Association of congenital cardiovascular malformations with 33 single nucleotide polymorphisms of selected cardiovascular disease-related genes. Birth Defects Res A Clin Mol Teratol 88:101-10
Lammer, Edward J; Chak, Jacqueline S; Iovannisci, David M et al. (2009) Chromosomal abnormalities among children born with conotruncal cardiac defects. Birth Defects Res A Clin Mol Teratol 85:30-5
Shaw, Gary M; Lu, Wei; Zhu, Huiping et al. (2009) 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects. BMC Med Genet 10:49
Hardin, J; Carmichael, S L; Selvin, S et al. (2009) Increased prevalence of cardiovascular defects among 56,709 California twin pairs. Am J Med Genet A 149A:877-86