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

神经管缺陷的遗传易感性：糖尿病/肥胖相关基因

• 批准号: 8136806
• 负责人: Huiping Zhu
• 金额: $ 17.34万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-06 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136806
• 关键词: Address; Affect; Animals; Antioxidants; Arts; Birth; Body mass index; Candidate Disease Gene; Collection; Complex; Congenital Abnormality; DNA; Data; Data Set; Development; Diabetes Mellitus; Diabetic mother; Embryo; Embryonic Development; Energy Metabolism; Environment; Environmental Risk Factor; Epidemiology; Ethnic Origin; Etiology; Evaluation; Family; Female of child bearing age; Folate; Future; Gene Targeting; Genes; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Genetic Variation; Glucose; Glucose Transporter; Human; Hyperglycemia; Individual; Infant; Insulin Resistance; Intake; Investigation; Joints; LEPR gene; Laboratories; Lead; Lipid Peroxidation; Maternal Age; Metabolic; Methods; Morbidity - disease rate; Mothers; Negative Finding; Neural Tube Defects; Neural Tube Development; Obesity; Oxidative Stress; PGC-1 protein; PPARG gene; Parents; Pathway interactions; Patients; Play; Population; Prediabetes syndrome; Predisposing Factor; Pregnancy; Prevention; Prevention strategy; Public Health; Race; Research; Research Personnel; Risk; Risk Assessment; Risk Factors; Role; SLC2A1 gene; Sampling; System; TCF7L2 gene; Transportation; Triad Acrylic Resin; United States; Variant; Woman; base; blood glucose regulation; gene interaction; genotyping technology; glucose transport; improved; in utero; innovation; malformation; maternal diabetes; mortality; non-diabetic; novel; public health relevance; trait

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.

描述（由研究者提供）：NTD是一组常见的结构畸形，与过度发病率和死亡率相关。在大多数NTD患者中无法确定特定的病原体，并且在这组患者中，该疾病被认为是一种遗传复杂的特征。母体糖尿病和孕前肥胖一直被认为是NTD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的NTD过多可能有一些共同的潜在机制。遗传上易患糖尿病/肥胖症的育龄妇女可能已经改变了葡萄糖稳态，即使她们是非糖尿病的;因此，产生高度受损的子宫内环境并将发育中的胚胎暴露于致畸分子（例如，额外的葡萄糖流量）。使发育中的胚胎本身易患糖尿病/肥胖相关致畸性的遗传因素可能会改变任何给定婴儿患NTD的风险。在这个应用程序中，我们建议调查遗传易感性的诱导NTDs的结果改变母体葡萄糖稳态，能量代谢和胚胎葡萄糖转运相关机制。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）的数据对候选基因和NTDs中的变异体之间的关联进行全面评估。这些基因中的一个或多个作为NTD的母体或胚胎风险因素的发现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。负面的发现，虽然不那么令人兴奋，也将有助于指导未来的研究工作，缩小候选基因的名单，纳入随后的研究。临床上，积极的发现可能会导致改善风险评估策略和遗传咨询受NTD影响的家庭。公共卫生关系：神经管缺陷是常见的严重出生缺陷，每年影响全球约324，000例出生和美国3，000例妊娠。糖尿病和肥胖是重要的公共卫生问题，也是NTD的危险因素。我们提出的研究将调查母体糖尿病/肥胖相关通路中的候选基因与NTD风险之间的关联。这些研究将有助于建立或反驳这些基因作为NTDs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，改善风险评估和遗传咨询受NTD影响的个人和家庭。