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（NTD）的病因学中起着关键作用。关于环境暴露、遗传因素和NTD风险之间关联的连续性结论受到这种结果罕见性的阻碍（例如，<1/1000出生在美国），和暴露评估研究之间的差异，以及坚持过于简单的病因模型。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，我们打算探索母体和胚胎的染色体，即，在中国山西省一个以高NTD率（约10/1000活产）、污染严重和营养状况差而闻名的地区，通过使用生物样本和通过已建立的基础设施收集的数据测量相关分析物和生物标志物，研究NTD病因学的内部化学环境。鉴定在胚胎发育期间使胚胎易于神经管闭合失败的人类基因一直具有挑战性。假设驱动的候选基因研究在识别可能预测NTD风险的常见变异方面并不成功。有限数量的候选基因的重新测序产生了一些遗传变异，尽管这些变异中没有一个单独是人类NTD的可靠预测因子。这使我们假设NTD，像其他复杂的疾病，可能会出现罕见的变异的组合效应。我们建议使用下一代测序技术来筛选基因组（外显子组）上的完整蛋白质编码区。我们预期产生一系列基因变异，包括单核苷酸变异（SNV）、插入/缺失（Indel）和结构变异（SV），这些变异有助于NTD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，生物样本和数据库将使我们能够继续探索NTD的基因组和染色体组，因为我们的研究工具包不断成熟。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的、基于确定性的和基于基因型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.