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

描述(由研究人员提供)：NTDS是一组常见的结构性畸形，与过度的发病率和死亡率有关。在大多数NTDS患者中，无法确定特定的病原体(S)，在这组患者中，这种情况被认为是一种复杂的遗传特征。长期以来，母亲糖尿病和孕前肥胖都被认为是NTDS的重要独立危险因素。到目前为止积累的证据表明，肥胖和糖尿病母亲所生婴儿的NTDS过量可能有一些共同的潜在机制。遗传上易患糖尿病/肥胖症的育龄妇女，即使不是糖尿病患者，也可能改变了血糖稳态；因此，在子宫环境中造成高度损害，并使发育中的胚胎暴露在致畸分子(例如，额外的葡萄糖通量)下。使发育中的胚胎本身易患糖尿病/肥胖相关畸形的遗传因素可能会改变任何特定婴儿患NTD的风险。在这一应用中，我们建议调查由于母体葡萄糖稳态、能量代谢和胚胎葡萄糖运输相关机制改变而导致NTDS的遗传易感性。将使用来自国家出生缺陷预防研究的大量NTDS病例-父母三联体(N=850)的数据，对候选基因中的变异与NTDS之间的关联进行全面评估。发现这些基因中的一个或多个是NTDS的母体或胚胎风险因素，将通过识别可能影响神经管发育的新基因和/或遗传途径来指导未来的研究工作。否定的发现虽然不那么令人兴奋，但也将通过缩小后续研究中纳入的候选基因列表来帮助指导未来的研究努力。临床上，积极的发现可能会改善受NTDS影响的家庭的风险评估策略和遗传咨询。与公共卫生相关：神经管缺陷是一种常见的严重出生缺陷，每年影响全球约324,000名新生儿和美国3,000名孕妇。糖尿病和肥胖症是重大的公共卫生问题，也是NTDS的风险因素。我们建议的研究将调查母亲糖尿病/肥胖相关途径中的候选基因与NTD风险之间的关联。这些研究将有助于确定或驳斥这些基因是NTDS的危险因素。这些信息将被用来指导未来的研究，并可能导致新的预防战略，改进风险评估，并为受非传染性疾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.