Conotruncal defects: genetic and nutritional risk

圆锥干缺陷：遗传和营养风险

• 批准号: 7091090
• 负责人: Edward James Lammer
• 金额: $ 40.4万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091090
• 关键词: cardiogenesis; clinical research; congenital heart disorder; developmental genetics; disease /disorder etiology; folate; genetic polymorphism; genetic susceptibility; health surveys; human subject; interview; nutrition related tag; nutritional epidemiology; transport proteins

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.

描述（由申请人提供）：本研究计划将调查圆锥动脉干心脏缺陷的营养和遗传风险因素。圆锥动脉干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方面的集体专业知识。该研究计划的三个目标将集中在圆锥动脉干缺陷的病因学上：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）研究两种叶酸转运蛋白叶酸受体-α和还原型叶酸载体的遗传变异;（3）寻找参与早期胚胎前心野发育的9个候选基因（NKX 2 -5、GATA 4、GATA 5、GATA 6、ZFPM 2、FOXH 1、MEF 2C、ISL 1和FGF 8）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使用一项新完成的加州基于人群的病例对照研究，该研究包括1999年至2004年间出生的360名圆锥动脉干缺陷婴儿和650名非畸形对照婴儿。它将结合联合收割机广泛的流行病学信息，从产妇访谈和营养调查与产妇和婴儿的基因分型，单体型和突变分析。这是对圆锥动脉干缺陷婴儿的最大的病例对照研究，将独特地产生基于人群的叶酸相关基因的基因型数据，并对编码转录因子的候选基因进行广泛的调查，这些转录因子指导前心野祖细胞分化为右心室和流出道的肌细胞。总的来说，这项研究计划试图提高我们对圆锥动脉干缺陷的遗传和营养原因的科学理解。如果研究确定了风险因素，将来将有可能预防这些心脏缺陷。由于圆锥动脉干缺陷会导致大量的发病率，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会导致预防性干预措施，这将大大有利于公共卫生和社会。