Study of Neural Tube Defects Etiology: Genome and Exposome

描述(由申请人提供)：基因-环境相互作用(GEI)在神经管缺陷(NTDS)的病因中起着关键作用。关于环境暴露、遗传因素和NTD风险之间的联系的明确结论一直受到这一结果的罕见(例如，美国的1/1000新生儿)、不同研究之间暴露评估的差异以及对过于简单的病因模型的坚持的阻碍。现在人们认识到，环境暴露的毒性效应是由改变人体内关键分子、细胞和生理过程的化学物质介导的。在拟议的研究项目中，我们打算通过使用生物样本和通过基础设施收集的数据来测量相关分析物和生物标记物，以探索母体和胚胎暴露，即NTD病因学中的内部化学环境。山西以NTD率高(约10/1000活产)、极其严重的污染和糟糕的营养状况而闻名，中国说。要确定使胚胎在胚胎发育过程中容易发生神经管闭合失败的人类基因(S)一直是具有挑战性的。假说驱动的候选基因研究未能成功识别可能预测NTD风险的常见变异。对有限数量的候选基因进行重新测序产生的遗传变异很少，尽管这些变异本身并不能很好地预测人类NTDS。这导致我们假设NTDS，像其他复杂的疾病一样，可能是由罕见变异的组合效应引起的。我们建议使用下一代测序技术来筛选基因组(外显子组)上完整的蛋白质编码区。我们预测了一系列基因变异的产量，包括单核苷酸变异(SNV)、插入/缺失(INDELL)和结构变异(SV)，这些变异有助于NTDS的表达。我们的研究结果将有助于确定母体暴露、母体营养、免疫反应、母体/胚胎遗传学和NTD风险之间的关系。此外，随着我们的研究工具不断成熟，生物样本和数据库将使我们能够继续探索NTDS的基因组和暴露组。通过我们的努力，将确定暴露和遗传标记。从这些研究中获得的信息可以为基于人群或有针对性、基于暴露和基于基因的风险评估战略提供基础。

DESCRIPTION (provided by applicant): Gene-environment interactions (GEI) play a critical role in the etiology of neural tube defect (NTDs). Definitive conclusions regarding the association amongst environmental exposures, genetic factors and NTD risk have been hampered by the rarity of this outcome (e.g., <1/1000 births in the US), and differences in exposure assessment between studies, as well as adherence to overly simplistic etiological models. It is now appreciated that the toxic effects of environmental exposures are mediated by chemicals that alter critical molecules, cells, and physiological processes inside the human body. In the proposed research project, we intend to explore the maternal and embryonic exposomes, i.e., the internal chemical environment in NTD etiology by measuring relevant analytes and biomarkers using biological samples and data collected through an established infrastructure in an area known for its high NTD rate (~10/1000 live birth), extremely heavy pollution, and poor nutritional status in Shanxi Province, China. To identify the human gene(s) that predispose the embryo to a neural tube closure failure during embryonic development has been challenging. Hypothesis-driven candidate gene studies were not successful in identifying common variants that may be predictive for NTD risk. Re-sequencing of a limited number of candidate genes has yielded few genetic variants, although none of these variants alone is a robust predictor of human NTDs. This leads us to postulate that NTDs, like other complex diseases, may arise from combinatorial effects of rare variants. We propose to use next-generation sequencing technologies to screen the complete protein coding regions on the genome (the exome). We anticipate the yield of a spectrum of gene variants including single nucleotide variations (SNV), insertion/deletion (Indel) and structural variations (SV) that contribute to the expression of NTDs. The results of our studies will help defining the relationships among maternal exposure, maternal nutrition, immune responses, maternal/embryonic genetics, and NTD risk. Moreover, the biological sample and data bank will allow us to continuously explore the genome and exposome of NTDs as our toolkit of investigation continues to mature. Exposure and genetic markers will be identified through our effort. The information derived from these studies could provide the foundation for population-based or targeted, exposure-based and genotype-based risk-assessment strategies.