Genetic Susceptibility of Neural Tube Defects: Diabetes/Obesity-related Genes

描述（由研究者提供）：热带病是一组常见的结构畸形，与高发病率和死亡率相关。在大多数被忽视热带病患者中，无法确定特定的病因，在这组患者中，该病被认为是一种复杂的遗传特征。长期以来，孕产妇糖尿病和孕前肥胖都被认为是被忽视热带病的重要独立危险因素。迄今为止积累的证据表明，肥胖母亲和糖尿病母亲所生婴儿中被忽视热带病的过量可能具有一些共同的潜在机制。遗传上易患糖尿病/肥胖的育龄妇女可能改变了葡萄糖稳态，即使她们不是糖尿病患者；因此，在子宫内产生高度受损的环境，并使发育中的胚胎暴露于致畸分子（例如，额外的葡萄糖通量）。使发育中的胚胎本身易患糖尿病/肥胖相关致畸的遗传因素可能会改变任何给定婴儿患NTD的风险。在这项应用中，我们建议研究由于母体葡萄糖稳态改变、能量代谢和胚胎葡萄糖转运相关机制而诱导NTDs的遗传易感性。将利用国家出生缺陷预防研究中大量收集的被忽视热带病病例-父母三联症（N=850）的数据，对候选基因变异与被忽视热带病之间的关系进行全面评估。通过识别可能影响神经管发育的新基因和/或遗传途径，暗示这些基因中的一个或多个是被忽视热带病的母体或胚胎危险因素的发现将指导未来的研究工作。消极的发现，虽然不那么令人兴奋，也将有助于指导未来的研究工作，缩小候选基因的列表，以纳入后续的研究。在临床上，积极的发现可以改善被忽视热带病影响的家庭的风险评估策略和遗传咨询。公共卫生相关性：神经管缺陷是一种常见的、严重的出生缺陷，全世界每年约有324000名新生儿和3000名孕妇受到影响。糖尿病和肥胖是重大的公共卫生问题，也是被忽视热带病的危险因素。我们拟开展的研究将探讨孕妇糖尿病/肥胖相关通路中候选基因与NTD风险之间的关系。这些研究将有助于确定或反驳这些基因是否为被忽视热带病的危险因素。这些信息将用于指导未来的研究，并可能导致新的预防策略、改进风险评估和为受被忽视热带病影响的个人和家庭提供遗传咨询。

DESCRIPTION (provided by investigator): NTDs are a group of common, structural malformation that is associated with excess morbidity and mortality. A specific etiologic agent(s) cannot be identified in the majority of individuals with NTDs, and in this group of patients the condition is believed to be a genetically complex trait. Both maternal diabetes and pre-pregnancy obesity have long been identified as significant independent risk factors for NTDs. Evidence accumulated to date suggests that the excess of NTDs among infants born to obese and to diabetic mothers may share some common underlying mechanisms. Child-bearing age women who are genetically susceptible to diabetes/obesity may have altered glucose homeostasis, even if they are non-diabetic; therefore, producing a highly compromised in utero environment and exposing the developing embryos to teratogenic molecules (e.g., extra glucose flux). Genetic factors predisposing the developing embryos themselves to diabetes/obesity-related teratogenicity may modify any given infants' risk of having an NTD. In this application, we propose to investigate the genetic susceptibility to the induction of NTDs as a result of altered maternal glucose homeostasis, energy metabolism and embryonic glucose transport related mechanisms. A comprehensive evaluation of the association between variants in the candidate genes and NTDs will be undertaken using data from a large collection of NTDs case-parent triads (N=850) from the National Birth Defects Prevention Study. Findings that implicate one or more of these genes as maternal or embryonic risk factors for NTDs will guide future research efforts, by identifying new genes and/or genetic pathways that may influence neural tube development. Negative findings, although less exciting, will also help to guide future research efforts by narrowing the list of candidate genes for inclusion in subsequent studies. Clinically, positive findings could lead to improved risk assessment strategies and genetic counseling for families affected by NTDs. PUBLIC HEALTH RELEVANCE: Neural tube defects are common, serious birth defects that affect approximately 324,000 births worldwide and 3,000 pregnancies in the United States annually. Diabetes and obesity are significant public health issues as well as risk factors for NTDs. Our proposed studies will investigate the association between candidate genes among maternal diabetes/obesity-related pathways and NTD risk. These studies will help to establish or refute these genes as NTDs risk factors. This information will be used to guide future studies and could lead to novel prevention strategies, improved risk assessments and genetic counseling for individuals and families affected by NTDs.