Folic Acid Prevention Pathways for ASD in High Risk Families

 描述（由申请人提供）：母体叶酸（叶酸的合成形式）是迄今为止确定的首批可改变因素之一，如果在怀孕期间服用，可能会将自闭症谱系障碍（ASD）的发生率降低40%。叶酸似乎可以预防ASD，特别是在遗传上易受叶酸依赖的一碳和甲基化代谢影响的母亲和儿童中，但这一发现需要复制。除了对神经发育至关重要外，叶酸还是甲基化反应（包括DNA甲基化）的主要甲基供体。在胚胎发生过程中，在基因组主动去甲基化和再甲基化的周期中，接近受孕的时间是足够甲基供应的特别关键时期。我们的初步数据显示，在ASD儿童的年幼兄弟姐妹中，叶酸补充剂与ASD风险的更大降低相关，降低了75%。此外，我们还发现了与母亲在出生组织（胎盘和脐带血）中未使用叶酸补充剂相关的DNA甲基化差异，这些基因具有核调节和大脑发育功能，可能对ASD有影响。 拟议工作的目标是利用来自两个高风险婴儿兄弟姐妹的大型前瞻性妊娠队列中的母子对的数据和样本，以研究通过母亲饮食和补充叶酸摄入预防ASD的具体途径。这项工作将建立在以前的研究基础上，通过检查前瞻性收集的暴露，在时间和剂量方面更加准确。我们将首先研究其他甲基供体B族维生素是否具有相关影响。我们将包括来自经验证的仪器的关于膳食和补充叶酸和B族维生素摄入的信息，以及来自母体妊娠早期血清、脐带血和胎儿胎盘组织的测量结果。我们将研究叶酸与遗传的相互作用， 易感因素最后，我们将通过识别与叶酸状态相关的DNA甲基化变化来增加对潜在机制的理解，并调查这些变化是否与自闭症大脑中观察到的甲基化模式重叠，使用创新方法，多平台，以及在组织类型和研究人群中复制，以解决与DNA甲基化测量相关的挑战。通过完成拟议的项目，我们将更好地了解叶酸与高风险家庭中ASD风险降低的相关性有多强，何时摄入量最相关以及在什么水平上，这种关联如何根据遗传易感性而不同，以及母体叶酸摄入量是否会以降低ASD风险的方式改变DNA甲基化谱。这些发现将具有重大的临床和公共卫生意义，为自闭症预防试验提供信息，并最终改变建议和政策。

 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.