Conotruncal defects: genetic and nutritional risk

描述（由申请人提供）：本研究项目将探讨圆锥状心脏缺陷的营养和遗传风险因素。圆锥锥体缺陷是复杂的人类先天性异常，其病因在很大程度上是未知的。这项研究利用了研究人员在分子流行病学、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。该研究计划的三个目标将集中在锥体缺陷的病因上：1)研究与叶酸代谢途径相关的五个基因的遗传变异（5,10-甲基四氢叶酸还原酶、甜菜碱同型半胱氨酸甲基转移酶1和2、n -乙酰转移酶1和胸苷酸合成酶）；2)研究叶酸受体α和还原性叶酸载体两种叶酸转运体的遗传变异；3)寻找参与早期胚胎前心区发育的9个候选基因（NKX2-5、GATA4、GATA5、GATA6、ZFPM2、FOXH1、MEF2C、ISL1和FGF8）的遗传变异。该研究项目有两个合作机构，奥克兰儿童医院研究所和加州出生缺陷监测项目。这项为期5年的综合研究计划将采用一项新完成的加利福尼亚人群病例对照研究，该研究由360名患有圆锥锥体缺陷的婴儿和650名未畸形的对照婴儿组成，这些婴儿在1999年至2004年间出生。它将结合来自孕产妇访谈和营养调查的广泛流行病学信息，以及母婴基因分型、单倍型和突变分析。这是最大的conotruncal缺陷婴儿病例对照研究，将独特地产生基于人群的叶酸相关基因的基因型数据，并广泛调查编码转录因子的候选基因，这些转录因子指导心脏前野祖细胞分化为右心室和流出道的肌细胞。总的来说，这个研究项目试图提高我们对圆锥锥体缺陷的遗传和营养原因的科学理解。如果这项研究确定了风险因素，将来就有可能预防这些心脏缺陷。由于圆锥锥体缺陷导致大量发病率，以及高昂的情感和经济成本，扩大我们对其原因的了解可能导致预防性干预措施，这将极大地有利于公共卫生和社会。

DESCRIPTION (provided by applicant): 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.