Prenatal and Neonatal Biologic Markers for Autism

描述(由研究人员提供)：拟议的研究将复制和扩展一项关于自闭症生物标记物的创新调查，使用来自母婴对的存档产前和新生儿样本。该项目由NIMH(R01 MH72565)资助，最初为期三年，该项目被称为自闭症早期标志物(EMA)研究，是第一项利用这些非常早期的生物标本来阐明自闭症潜在原因的大型、基于人群的病例对照研究。这项研究包括三组儿童：患有自闭症谱系障碍(ASD)的儿童，患有智力低下(MR)但不是自闭症的儿童，以及从普通人群中随机选择的儿童(GP)。EMA研究的科学和概念重点是免疫和遗传易感因素、环境暴露以及基因与环境的相互作用，这些因素直接作用于神经发育，或通过免疫系统的失调间接作用。第一个供资周期的初步结果表明，与对照儿童的母亲相比，患有自闭症儿童的母亲的孕中期免疫状况失调。选定的细胞因子(干扰素-γ、白介素4、白介素5、白介素6)水平升高，母亲对胎儿脑蛋白的抗体在病例中比对照母亲更常见。此外，选择免疫功能基因的多态在患有自闭症的母亲(干扰素-伽马)和儿童(白介素6)中更常见。这项续签申请寻求额外5年的资金，通过在1200对母婴对(400对ASD、400名MR、400名GP对照)中进行更大规模的病例对照研究，并增加以家庭为基础的部分，其中包括60名ASD病例的兄弟姐妹和60名MR对照的兄弟姐妹。将对样本进行免疫系统功能(细胞因子、趋化因子、胎儿大脑抗体)、环境暴露(有机氯农药、多氯联苯和多溴二苯醚)以及候选单核苷酸多态(SNPs)和拷贝数变异(CNV)的分析，以调节免疫功能、异体新陈代谢和解毒以及母婴转运。如此大的样本量将确保有足够的统计能力来检查相对罕见的暴露、ASD的表型亚组和种族亚组。这项研究的发现可能会确定进一步研究生理机制的领域，并将提供关于未受影响的对照的标准化数据。从长远来看，更好地了解潜在的生物学可能会为早期干预提供适当的策略，并有助于最终预防这种往往是毁灭性的、通常是终生的残疾。 公共卫生相关性：这项拟议的研究将继续调查以前由NIH资助的自闭症的产前和新生儿生物标记。这项新研究的目标是通过评估储存的自闭症儿童、其他发育障碍儿童和人群对照儿童的产前(母亲)和新生儿血液样本，进一步调查产前和新生儿免疫因素、遗传易感因素和环境暴露的作用。我们预计，这项研究的结果将有助于确定增加自闭症风险的因素，并可能最终预防自闭症和相关疾病。

DESCRIPTION (provided by investigator): The proposed study will replicate and extend an innovative investigation of biologic markers for autism using archived prenatal and newborn specimens from mother-baby pairs. Funded by the NIMH (R01 MH72565) for an initial three-year period, this project, known as the Early Markers for Autism (EMA) Study, is the first large, population-based case-control study to utilize these very early biologic specimens to elucidate underlying causes of autism. The study includes three groups: children with autism spectrum disorders (ASD), children with mental retardation (MR) but not autism, and children selected at random from the general population (GP). The scientific and conceptual focus of the EMA Study is on immunologic and genetic susceptibility factors, environmental exposures, and the interplay of genes with environment, operating either directly on neurodevelopment, or indirectly via dysregulation of the immune system. Preliminary results from the first funding cycle indicate that the mid-pregnancy immune profile of mothers of children with ASD is dysregulated in comparison to mothers of control children. Levels of select cytokines (IFN-gamma, IL-4, IL-5, IL-6) are elevated, and maternal antibodies to fetal brain proteins are present more often in case than control mothers. In addition, polymorphisms in select immune function genes are more common in mothers (IFN-gamma) and children (IL-6) with autism. This renewal application seeks funding for an additional 5-year period to further these initial findings by conducting a much larger case-control study among a new sample of 1,200 mother-baby pairs (400 ASD, 400 MR, 400 GP controls), with an added family-based component that includes 60 siblings of ASD cases and 60 siblings of MR controls. Specimens will be analyzed for markers of immune system function (cytokines, chemokines, antibodies to fetal brain), environmental exposures (organochlorine pesticides, PCBs, and PBDEs), and candidate single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) regulating immune function, xenobiotic metabolism and detoxification, and maternal-fetal transport. This large sample size will ensure sufficient statistical power for the examination of relatively rare exposures, phenotypic subgroups of ASD, and ethnic subgroups. Findings from this study will likely define areas for further investigations of physiologic mechanism and will provide normative data on unaffected controls. In the long-term, a better understanding of the underlying biology may suggest appropriate strategies for early intervention and contribute to the eventual prevention of this often devastating and usually life-long disability. PUBLIC HEALTH RELEVANCE: The proposed study will continue an investigation of prenatal and newborn biologic markers for autism previously funded by NIH. The goal of the new study is to investigate further the role of prenatal and newborn immunologic factors, genetic susceptibility factors, and environmental exposures by evaluating stored prenatal (maternal) and newborn blood specimens for children with autism, children with other developmental disabilities, and population controls. We anticipate that the results of this study will contribute to identifying factors that increase the risk for autism and may lead to eventual prevention of autism and related disorders.