Gene /environment interactions and risks of conotruncal heart defects

遗传易感性和环境暴露的结合被怀疑是造成常见人类先天性畸形的重要原因。妊娠早期服用叶酸可降低圆锥状心脏畸形的风险，但其机制尚不清楚。在流行病学和实验证据的基础上，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有直接的致畸作用。其次，我们假设母体高同型半胱氨酸抑制n -甲基- d -天冬氨酸型谷氨酸（NMDA）受体的功能，并且同型半胱氨酸可能与其他也抑制NMDA受体功能的致畸物相互作用。该项目的总体目标是通过整合流行病学数据（3000例病例和对照）以及基于聚合酶链反应的基因分型对人类遗传变异的测量来检验这些假设。该项目有三个具体目的：目的1：分析在母体叶酸摄入量发生变化的情况下，母体或婴儿叶酸途径基因的遗传变异是否会改变圆锥锥体畸形的风险。目的2：分析暴露于NMDA受体拮抗剂的妇女分娩婴儿或胎儿conotruncal畸形的风险是否增加；而母体叶酸水平低或叶酸代谢异常是否会加剧这种影响，为第二种假设提供了关键检验。目的3：分析摄入较高或较低水平的特定营养素的女性是否有更高的风险生育患有圆锥锥体畸形的后代，解决叶酸、同型半胱氨酸和其他营养素与早期心脏发育之间相互关系的信息缺乏问题。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。

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.