Metabolic Biomarkers of Autism: Predictive Potential and Genetic Susceptibility

自闭症的代谢生物标志物：预测潜力和遗传易感性

• 批准号: 7141391
• 负责人: Sandra Jill James
• 金额: $ 36.29万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-10 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7141391
• 关键词: DNA methylation; aminoacid metabolism; autism; biomarker; child behavior disorders; child mental disorders; clinical research; disease /disorder proneness /risk; early diagnosis; gene expression; gene interaction; genetic polymorphism; genetic susceptibility; glutathione; human subject; intermolecular interaction; mental disorder diagnosis; mental health epidemiology; metabolism disorder; methionine; middle childhood (6-11); oxidative stress; patient oriented research; preschool child (1-5)

DESCRIPTION (provided by applicant): Autism is a behaviorally-defined neurodevelopmental disorder with a CDC-reported prevalence of approximately 1 in 166 children in the US and future societal costs estimates up to $43 billion per year. Despite the urgency to uncover the biologic basis of autism, research progress has been slow. Although both genetic and environmental factors are thought to be involved, none as yet have been reproducibly identified. The metabolic basis for autism has received much less research attention despite the fact that chronic biochemical imbalance is often a primary factor in the development of complex disease. The metabolic phenotype of an individual reflects the influence of endogenous and exogenous factors on genotype. As such, it provides a window through which the interactive impact of genes and environment may be viewed and relevant susceptibility factors identified. Based on our recent discovery that children with autism exhibit abnormal methionine and glutathione metabolism, we hypothesize that the observed metabolic imbalance results in increased oxidative stress and impaired methylation capacity that may contribute, in part, to the development and clinical manifestations of autism. We further hypothesize that the abnormal metabolic profile will be associated with increased frequency of genetic polymorphisms that functionally affect methionine and glutathione metabolism. Aim 1 will determine whether the severity and specificity of metabolite imbalance is associated with quantitative measures of cognition and behavior and whether the metabolic profile has positive predictive value as a biochemical test for autism to support the behavioral diagnosis. Aim 2 will prospectively investigate whether the abnormal metabolic profile is detectable in high risk toddlers before the behavioral testing is possible as a means to expedite early intervention and treatment strategies to improve outcome. Mechanistic Aim 3 will establish whether cells from autistic children exhibit evidence of oxidative damage, increased vulnerability to oxidative stress, and/or DNA hypomethylation. Using the metabolic profile as a phenotypic map for the selection of candidate genes, Aim 4 will determine whether autism is associated with specific genetic polymorphisms, gene-gene and gene- metabolite interactions that affect methionine and glutathione metabolism. The knowledge gained from this proposal will add a new metabolic dimension to the diagnosis and clinical management of children with autism. The identification of a metabolic endophenotype associated with increased risk of autism will provide new insights into treatment options and new directions for translational research. The public health significance of this proposal is the clinical translation of these findings into early detection and improved diagnosis, better understanding of autism-related pathology, and new targeted intervention strategies to improve the health and clinical outcome of children with autism.

描述（由申请人提供）：自闭症是一种行为定义的神经发育障碍，美国疾病控制与预防中心报告的患病率约为166名儿童中有1名，未来的社会成本估计每年高达430亿美元。尽管迫切需要揭示自闭症的生物学基础，但研究进展缓慢。虽然遗传和环境因素都被认为与之有关，但迄今为止还没有一个可重复地确定。尽管慢性生化失衡往往是复杂疾病发展的主要因素，但自闭症的代谢基础却很少受到研究的关注。个体的代谢表型反映了内源和外源因素对基因型的影响。因此，它提供了一个窗口，通过它可以观察基因和环境的相互影响，并确定相关的易感性因素。基于我们最近的发现，自闭症儿童表现出异常的蛋氨酸和谷胱甘肽代谢，我们假设观察到的代谢失衡导致氧化应激增加和谷胱甘肽甲基化能力受损，这可能在一定程度上导致自闭症的发展和临床表现。我们进一步假设，异常代谢谱将与基因多态性频率增加有关，这些多态性在功能上影响蛋氨酸和谷胱甘肽的代谢。目的1将确定代谢物失衡的严重程度和特异性是否与认知和行为的定量测量相关，以及代谢谱是否作为自闭症的生化测试具有积极的预测价值，以支持行为诊断。目的2将前瞻性地研究在行为测试之前是否可以在高危幼儿中检测到异常代谢谱，作为加快早期干预和治疗策略以改善结果的手段。Mechanistic Aim 3将确定自闭症儿童的细胞是否表现出氧化损伤、对氧化应激的脆弱性增加和/或DNA低甲基化的证据。利用代谢谱作为选择候选基因的表型图谱，Aim 4将确定自闭症是否与影响蛋氨酸和谷胱甘肽代谢的特定遗传多态性、基因-基因和基因-代谢物相互作用有关。从这一建议中获得的知识将为自闭症儿童的诊断和临床管理增加一个新的代谢维度。识别与自闭症风险增加相关的代谢内表型将为治疗方案提供新的见解，并为转化研究提供新的方向。该建议的公共卫生意义在于将这些发现转化为早期发现和改进诊断，更好地了解自闭症相关病理，以及新的有针对性的干预策略，以改善自闭症儿童的健康和临床结果。