Gene /environment interactions and risks of conotruncal heart defects

基因/环境相互作用和圆锥干心脏缺陷的风险

• 批准号: 7115379
• 负责人: GARY M SHAW
• 金额: $ 24.55万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7115379
• 关键词: NMDA receptors; clinical research; congenital heart disorder; dietary constituent; embryo /fetus drug adverse effect; embryo /fetus toxicology; folate deficiency; gene environment interaction; genetic polymorphism; genetic susceptibility; homocysteine; human subject; mother /embryo /fetus nutrition; nutrient interaction; nutrition related tag; questionnaires; teratogens

The combination of genetic susceptibility and environmental exposure is suspected of contributing significantly to the occurrence of common human congenital malformations. Folic acid use early in pregnancy reduces the risk of conotruncal heart malformations, but the mechanism underlying this reduction is unknown. On the basis of epidemiologic and experimental evidence, two unifying hypotheses have emerged. First, we hypothesize that folate insufficiency may have a direct teratogenic effect on cells that utilize folate-specific binding and transport proteins. Second, we hypothesize that maternal hyperhomocysteine inhibits the function of the N-methyl-D-aspartate type of glutamate (NMDA) receptor, and that homocysteine may interact with other teratogens that also inhibit NMDA receptor function. The overall goal of this project is to test each of these hypotheses by integrating epidemiologic data (3000 cases and controls) with the measurement of human genetic variation by polymerase chain reaction-based genotyping. There are 3 specific aims of this project: Aim 1: to analyze whether genetic variations of maternal or infant folate- pathway genes modify risk of conotruncal malformations, in the presence of variations in maternal folate intake. Aim 2: to analyze whether women exposed to NMDA receptor antagonists are at increased risk of delivering infant or fetuses with conotruncal malformation; and whether this effect is exacerbated with low maternal folate or abnormal folate metabolism, providing a key test of the second hypothesis. Aim 3: to analyze if women who consume higher or lower levels of selected nutrients are at increased risk of delivering offspring with conotruncal malformations, addressing the paucity of information about the interrelations among folate, homocysteine and other nutrients on early heart development. Understanding the mechanisms by which nutrition, genetic background and environmental exposures interact will substantially increase the probability of developmental malformations.

怀疑遗传敏感性和环境暴露的结合可显着促进人类普通先天性畸形的发生。妊娠早期使用叶酸会降低心脏畸形的风险，但是这种减少的机制尚不清楚。根据流行病学和实验证据，出现了两个统一的假设。首先，我们假设叶酸不足可能对利用叶酸特异性结合和转运蛋白的细胞具有直接的致畸作用。其次，我们假设母体的女性超半胱氨酸抑制了N-甲基-D-天冬氨酸类型的谷氨酸（NMDA）受体的功能，并且同型半胱氨酸可能与其他也抑制NMDA受体功能的te​​ratogen相互作用。该项目的总体目标是通过将流行病学数据（3000例病例和对照）与基于聚合酶链反应的基因分型进行测量来测量这些假设。该项目有3个特定目的：目标1：分析母体或婴儿叶酸途径基因的遗传变异是否会改变构成畸形的风险，在孕产妇叶酸摄入量变化的情况下。目标2：分析暴露于NMDA受体拮抗剂的妇女是否有增加婴儿或胎儿畸形的胎儿的风险；以及这种作用是否被低母体叶酸或异常叶酸代谢加剧，提供了第二个假设的关键检验。目标3：分析消耗较高或较低水平的养分的妇女是否有增加与共同畸形的后代的风险，以解决有关早期心脏发育中有关叶酸，同胱氨酸和其他营养素之间相互关系的信息的匮乏。了解营养，遗传背景和环境暴露相互作用的机制将大大增加发育畸形的可能性。