Prenatal and Neonatal Biologic Markers for Autism

描述（由研究者提供）：拟议的研究将复制和扩展自闭症生物标志物的创新调查，使用存档的产前和新生儿标本，从母亲-婴儿对。由NIMH（R 01 MH 72565）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，是第一个大型的，基于人群的病例对照研究，利用这些非常早期的生物标本来阐明自闭症的根本原因。这项研究包括三组：自闭症谱系障碍（ASD）儿童，智力迟钝（MR）但不是自闭症的儿童，以及从普通人群（GP）中随机选择的儿童。EMA研究的科学和概念重点是免疫和遗传易感性因素，环境暴露以及基因与环境的相互作用，直接影响神经发育或间接通过免疫系统失调。第一个供资周期的初步结果表明，与对照儿童的母亲相比，ASD儿童的母亲怀孕中期免疫状况失调。选定的细胞因子（IFN-γ，IL-4，IL-5，IL-6）的水平升高，母体抗体胎儿脑蛋白的情况下比对照母亲更经常存在。此外，选择免疫功能基因的多态性在患有自闭症的母亲（IFN-γ）和儿童（IL-6）中更常见。该更新申请寻求额外5年的资金，以进一步这些初步研究结果，在1，200对母婴（400名ASD，400名MR，400名GP对照）的新样本中进行更大规模的病例对照研究，增加了基于家庭的组成部分，包括60名ASD病例的兄弟姐妹和60名MR对照的兄弟姐妹。将分析标本的免疫系统功能标志物（细胞因子、趋化因子、胎儿脑抗体）、环境暴露（有机氯农药、多氯联苯和多溴二苯醚）、候选单核苷酸多态性（SNP）和拷贝数变异（CNV），这些标志物调节免疫功能、异生物质代谢和解毒以及母胎转运。这种大样本量将确保有足够的统计功效来检查相对罕见的暴露、ASD的表型亚组和种族亚组。本研究的结果可能会定义进一步研究生理机制的领域，并将提供未受影响对照的规范性数据。从长远来看，更好地了解潜在的生物学可能会建议早期干预的适当战略，并有助于最终预防这种往往是毁灭性的，通常是终身的残疾。

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.