Folic Acid Prevention Pathways for ASD in High Risk Families

高危家庭中自闭症谱系障碍 (ASD) 的叶酸预防途径

• 批准号: 8917743
• 负责人: Rebecca Jean Schmidt
• 金额: $ 63.73万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8917743
• 关键词: Address; Affect; Age; Autistic Disorder; Birth; Brain; Carbon; Child; Choline; Clinical; Complex; Conceptions; DNA Methylation; Data; Development; Developmental Gene; Diet; Disease; Dose; Embryonic Development; Environment; Environmental Risk Factor; Epigenetic Process; Etiology; Exposure to; Family; Fetal Tissues; First Pregnancy Trimester; Folic Acid; Future; Gene Targeting; Genes; Genetic; Genetic Predisposition to Disease; Genome; Goals; Histocompatibility Testing; Individual; Intake; MTHFR gene; Measurement; Menstruation; Metabolism; Methods; Methylation; Mothers; Nuclear; Nutrient; Pathway interactions; Placenta; Policies; Population Study; Predisposition; Pregnancy; Prevention; Prevention trial; Prospective Studies; Public Health; Reaction; Recommendation; Risk; Role; Sampling; Serum; Siblings; Side; Supplementation; Time; Tissues; Umbilical Cord Blood; Variant; Vitamin B 12; Vitamin B Complex; Work; autism spectrum disorder; base; brain tissue; cohort; critical period; demethylation; disorder risk; fetal; genetic risk factor; high risk; high risk infant; implantation; in utero; innovation; instrument; methylation biomarker; methylation pattern; neurodevelopment; nutrition; prevent; prospective; protective effect; public health relevance; response

 DESCRIPTION (provided by applicant): Maternal folic acid, the synthetic form of folate, is one of the first modifiable factors identified to date with the potential to reduce occurrence of autis spectrum disorders (ASD) by 40% if taken near conception. Folic acid appears to protect against ASD especially in mothers and children who are genetically susceptible to inefficient folate-dependent one-carbon and methylation metabolism, but this finding needs replication. In addition to being essential for neurodevelopment, folate is a primary methyl-donor for methylation reactions, including DNA methylation. The time near conception is an especially critical period for adequate methyl supply during cycles of active demethylation and re-methylation of the genome during embryogenesis. Our preliminary data show that folic acid supplementation is associated with even greater reductions in ASD risk, by 75%, in younger siblings of children with ASD. In addition, we found DNA methylation differences associated with no maternal use of folic acid supplements in birth tissues (placenta and cord blood) for genes with nuclear regulatory and brain development functions that could have implications for ASD. The goal of the proposed work is to leverage data and samples from mother-child pairs in two large prospective pregnancy cohorts of high-risk infant siblings to examine specific pathways for prevention of ASD through maternal dietary and supplemental folate intake. This work will build on previous studies by examining exposures collected prospectively, with more accuracy in terms of timing and dose. We will be first to examine whether other methyl-donor B-vitamins have associated effects. We will include information on dietary and supplemental folate and B-vitamin intake from validated instruments, and measurements from maternal first trimester serum, cord blood, and fetal placental tissue. We will examine folic acid interactions with genetic susceptibility factors. Finally, we will increase understanding of the underlying mechanisms by identifying DNA methylation changes associated with folate status, and investigate whether these changes overlap with methylation patterns observed in autistic brains, using innovative methods, multiple platforms, and replication across tissue type and study population, to address challenges associated with DNA methylation measurement. Through completion of the proposed project, we will gain a better understanding of how strongly folic acid is associated with reduced risk of ASD in high-risk families, when intake is most associated and at what levels, how this association differs based on genetic susceptibility, and whether maternal folic acid intake alters DNA methylation profiles in ways that could decrease ASD risk. These findings will have great clinical and public health implications, informing autism prevention trial and ultimately changes in recommendations and policy.

 描述（由适用提供）：叶酸的合成形式母体叶酸是迄今为止确定的第一个可修改因素之一，如果近乎概念，则可能将Autis Spectrum Disormanders（ASD）降低40％。叶酸似乎可以预防ASD，尤其是在母亲和儿童中，这些母亲和儿童通常易于无效的叶酸依赖性的一碳和甲基化代谢，但是这一发现需要复制。除了对神经发育至关重要之外，叶酸是甲基反应（包括DNA甲基化）的原代甲基二谱。近概念的时间是在胚胎发生过程中活跃脱甲基化和重新甲基化的循环中足够的甲基供应的特别关键时期。我们的初步数据表明，在ASD儿童的年轻兄弟姐妹中，补充叶酸的降低与ASD风险的降低更大有关。此外，我们发现与可能对ASD具有影响的核调节性和脑发育功能的基因相关的DNA甲基化差异与出生组织中的叶酸补充剂（plapeta和脐带血）无关。拟议工作的目的是利用两个大型预期怀孕同胞中的母子对的数据和样本，以检查通过母子饮食和补充叶酸摄入量来预防ASD的特定途径。这项工作将基于先前的研究，通过前瞻性检查的暴露，并在时间和剂量方面更准确。我们将首先检查其他甲基甲基甲基B-VITAMIN是否具有相关作用。我们将包括有关饮食和补充叶酸和B-维生素摄入量的信息，以及从孕期孕早期血清，脐带血和胎儿胎盘组织的测量。我们将检查与遗传的叶酸相互作用 易感因素。最后，我们将通过鉴定与叶酸状态相关的DNA甲基化变化来提高对潜在机制的了解，并研究这些变化是否与在加速大脑中观察到的甲基化模式重叠，使用创新方法，多种平台以及跨组织类型和研究人群的复制来解决与DNA甲基化测量相关的挑战。通过完成拟议项目，我们将更好地了解叶酸与高危家族中ASD风险的强烈相关，何时摄入量最相关，在什么水平上，该关联基于遗传易感性以及母体叶酸的摄入量是否会改变降低ASD风险的DNA甲基化谱。这些发现将具有很大的临床和公共卫生影响，从而为预防自闭症的试验提供了信息，并最终改变了建议和政策的变化。