Project 2: Genetic Epidemiology of Neurodevelopmental Metal Toxicity

最近的数据显示，锰和砷等金属日益引起公众健康关注 证明了它们对大脑发育的神经毒性。然而，遗传易感性对这些疾病的作用 有毒金属尚不清楚。此外，虽然铅中毒已被广泛研究，遗传 对其毒性的敏感性尚不清楚。基因-环境的系统研究 相互作用将直接影响我们对金属如何诱发毒性的理解， 对潜在治疗和预防措施的生物学见解。在这个项目中，我们将评估来自3个 金属和神经发育的队列研究。一个在发展中国家孟加拉国， 风险敞口异常高，其中一个在墨西哥，一个中等收入国家， 中度高，一个在发达国家-（美国）在焦油溪，OK，那里的接触是 美国有毒废物处理场附近的一个社区的代表。Tar Creek是一个超级基金Megasite和前 金属矿社区这些群体的成功聚集为进一步的 对金属的遗传易感性的研究。我们的3个队列合并产生了2600名儿童的样本， 金属暴露的前瞻性数据和重复的神经表型测量;有足够的把握发现 并验证遗传易感基因/SNP。使用全基因组方法，我们将发现 在发现阶段的易感性变异，然后在一个独立的样本中验证发现， 儿童，同时控制多重比较。此外，我们将与项目3（遗传学）整合， 金属神经毒性机制）使用确定与金属毒性相关的其他生物学途径 现有技术水平的siRNA技术来鉴定促进/抑制金属毒性的基因/途径。这个项目 这可能是第一个大规模的协调研究遗传易感性的金属毒性， 为金属产生毒性的机制提供生物学见解。

Metals such as manganese and arsenic are of increasing public health concern since recent data demonstrates their neurotoxicity to the developing brain. However, the role of genetic susceptibility to these toxic metals is unknown. Furthermore, while lead poisoning has been studied extensively, genetic susceptibility to its toxicity is not well understood. A systematic approach to studying gene-environment interaction would have immediate impact on our understanding of how metals induce toxicity and provide biological insight for potential treatment and prevention measures. In this project we will assess data from 3 cohort studies of metals and neurodevelopment. One in a developing country-Bangladesh, where metal exposures are unusually high, one in Mexico, a middle income country where metal exposures are moderately high, and one in a developed Country- (United States) in Tar Creek, OK, where exposure are representative of a community near a US toxic waste site. Tar Creek is a Superfund Megasite and former metal mining community. The success in assembling these cohorts has laid the groundwork for further research in genetic susceptibility to metals. Our 3 cohorts combined yield a sample of 2600 children with prospective data on metal exposure, and repeated neurophenotype measures; sufficient power to discover and to validate genetic susceptibility genes/SNPs. Using a genome-wide approach, we will discover susceptibility variants in a Discovery phase, and then Validate our findings in an independent sample of children while controlling for multiple comparisons. Furthermore, we will integrate with Project 3 (Genetic Mechanisms of Metal Neurotoxicity) to determine other biological pathways relevant to metal toxicity using state of the art siRNA technology to identify genes/pathways which prorriote/inhibit metal toxicity. This project represents perhaps the first large scale coordinated study of genetic susceptibility to metal toxicity and will provide biological insight into the mechanisms by which metals produce toxicity.