Maternal and Embryonic Causes of Spina Bifida

脊柱裂的母体和胚胎原因

• 批准号: 7216691
• 负责人: LAURA E. MITCHELL
• 金额: $ 53.44万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7216691
• 关键词: Accounting; Address; Candidate Disease Gene; Collection; Complex; Condition; Congenital Abnormality; Data; Data Collection; Databases; Embryo; Environment; Environmental Exposure; Environmental Risk Factor; Etiology; Evaluation; Experimental Designs; Exposure to; Family; Folate; Foundations; Funding; Genes; Genetic; Genetic Counseling; Genotype; Goals; Grant; Human; Individual; Institutes; Methods; Modeling; Morbidity - disease rate; National Institute of Child Health and Human Development; Numbers; Pathway interactions; Patients; Predisposition; Prevention strategy; Protocols documentation; Research Design; Risk; Risk Assessment; Role playing therapy; Sample Size; Spinal Dysraphism; Thinking; United States National Institutes of Health; Variant; Work; base; design; fetal; folic acid metabolism; gene interaction; genetic risk factor; genetic variant; improved; malformation; mortality; novel; tool; trait

DESCRIPTION (provided by applicant): Spina bifida is a relatively 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 spina bifida, and in this group of patients the condition is believed to be a genetically complex trait. As with other complex human traits, spina bifida is thought to be influenced by common genetic variants that, individually, may have only a small to moderate effect on risk. However, efforts to identify such variants have been hampered by lack of replication. This is, at least in part, attributable to overly simplistic models of disease etiology, poor experimental design and insufficient sample size. The studies proposed in this application are designed to minimize these limitations while addressing the primary study hypothesis: common variants in folate-related genes contribute to the risk of spina bifida. Our evaluation of this hypothesis will consider the roles played by both the maternal and embryonic genotype, and the possibility that the interplay of genes and environmental risk factors may be more relevant to the risk of spina bifida than is the independent main effect of any one susceptibility locus. This twice revised, competitive renewal application builds on our previous work by: (1) extending our collection of families, (2) increasing the number of folate-related genes to be evaluated, and moving from a single-SNP to a multiple-SNP per gene approach, (3) incorporating new methods for the assessment of complex interactions, and (4) extending our recently developed, likelihood- based approach for evaluation of maternal and embryonic genetic effects to allow for missing data, genotyping errors and both gene-environment and gene-gene interactions. These studies will help to define the relationship between spina bifida risk and variation in folate-related genes. Such an understanding will provide improved content for genetic counseling, including the possibility of genotype-based, risk- assessment, and the foundation for novel new prevention strategies for this common, serious malformation.

描述（由申请人提供）：脊柱裂是一种相对常见的结构畸形，与发病率过多和死亡率有关。在大多数患有脊柱裂的个体中，无法鉴定出特定的病因学剂，并且在这组患者中，该病情被认为是遗传复杂的特征。与其他复杂的人类性状一样，脊柱裂的人被认为受到常见遗传变异的影响，这种变异单独可能对风险产生小至中等影响。但是，由于缺乏复制，识别这种变体的努力受到了阻碍。至少部分归因于过度简单的疾病病因，实验设计差和样本量不足。本应用中提出的研究旨在最大程度地减少这些局限性，同时解决主要研究假设：叶酸相关基因中的常见变体有助于脊柱裂的风险。我们对这一假设的评估将考虑母体和胚胎基因型所扮演的角色，以及基因和环境风险因素的相互作用可能与脊柱裂的风险更重要，而不是任何一个敏感性基因座的独立主要效果。这两次修订，竞争性更新的申请基于我们以前的工作：（1）扩大我们的家庭收集，（2）增加要评估的叶酸相关基因的数量，并从单个SNP转移到每个基因的多个SNP到每个基因的多个SNP，（3）纳入了新的方法，以评估我们最近开发的复杂相互作用，以及（4），（4）仿效的效果，（4）（4）（4）（4）（4）（4）（4）（4）（4）（4）（4）（4）（4）（4）（4）（4）允许缺少数据，基因分型误差以及基因环境和基因 - 基因相互作用。这些研究将有助于定义脊柱裂风险与叶酸相关基因变异之间的关系。这种理解将为遗传咨询提供改进的内容，包括基于基因型的风险评估的可能性以及这种常见，严重畸形的新型新预防策略的基础。