神经发育关键期环境危险因素与孤独症谱系障碍遗传特征关系的人群研究

The etiology of autism spectrum disorders (ASD), largely restricting the prevention and treatment of the ASD, remains an unsolved global scientific problem. Currently it is widely acknowledged by researchers that genetic combined with environmental factors contribute to the induction of ASD, of which the environmental risk factors during the critical window period are most compelling. However the evident link between this critical window period in neurodevelopment and the genetic variation of ASD is still missing. This study, based on previous research, resorts to the methodology of epidemiological studies and multidisciplinary approaches to investigate the impact of environmental risk factors, including the exposure with endocrine disrupting compounds (EDCs), nutrition, lifestyle and physical and mental health status in fetal and infants, on ASD and its possible mechanism. Meanwhile we aim to examine genetic mutational properties within core families of ASD probands, evaluate the role of environmental risk factors in children with ASD under difference circumstances of genetic characteristics and monitor early developmental characteristics of the children with ASD. This project will not only illustrate the impact of environmental risk factors on the prevalence of ASD during critical neurodevelopmental period and its redox mechanism, which would assist us to clarify the relationship between these environmental risk factors and the genetic variation of ASD, but also provide prospective population data for the early development of nervous system in children with ASD deficiency in China. Therefore this study is significant as it lays the foundation for the exploration of the etiology of ASD and provides direct evidence for prevention, early intervention and treatment of ASD.

孤独症谱系障碍（ASD）病因是目前尚未解决的科学问题，它制约了ASD预防及治疗成为研究热点。目前公认遗传与环境因素协同引发ASD，在神经发育关键窗口期的环境危险因素引人注目，但该期与ASD遗传变异特征关系的人群直接证据缺乏。本项目在以往研究的基础上应用流行病学研究方法和多学科手段，使用回顾和前瞻性方法调查胎、婴儿期环境内分泌干扰化合物（EDCs）相关的环境毒物暴露、营养、生活方式及身心健康等环境危险因素对ASD患病的影响及可能机制；测定ASD先证者核心家庭的遗传变异特征并分析在不同遗传特征下环境危险因素的作用；观测ASD早期发育特征。本项目将阐明在人神经发育关键期的环境危险因素对ASD患病的影响及其氧化还原机制；这些环境危险因素与ASD致病基因遗传变异的关系；提供我国尚缺乏的ASD患儿神经系统发育早期特征的前瞻性人群资料。为探讨ASD病因提供依据，为预防、早期干预和治疗ASD提供直接证据。

孤独症谱系障碍（ASD）病因尚不清楚，这制约了ASD预防及治疗。目前公认遗传与环境因素协同引发ASD，其中神经发育关键窗口期的环境危险因素尤其引发关注。本项目应用回顾和前瞻性调查方法，调查了ASD先证者核心家庭的遗传变异特征；探究从胎儿期到儿童期环境危险因素对子代神经行为发育包括ASD相关早期神经行为特征的影响及炎症机制；测量ASD早期行为特征。本项目结果1.病例对照研究发现，RELN基因单核苷酸多态性（rs2229864、rs2229864-rs736707）与ASD发病风险相关，RELN基因单核苷酸多态性（rs736707）与ASD感觉问题及社交问题严重程度相关。IL-6-572CC单核苷酸多态性（rs1800796）与血清白细胞介素(IL)-6和髓磷脂碱性蛋白（MBP）水平显著升高相关，但不影响ASD的风险和症状严重程度；2.本项目建立了“天津市母婴健康教育与服务队列（Tianjin Maternal and Child Health Education and Service Cohort , 简称TMCHESC）”。队列研究发现，妊娠前体重指数（BMI）与婴儿6月龄手眼协调领域发育商（DQ）降低有关，产前超重/肥胖+GDM与婴幼儿6~12月龄个人社会领域发育商（BQ）及社交/几何图片注视时间百分比降低有关。母亲孕期平均IL-6水平在妊娠前肥胖与婴儿6月龄手眼协调关系及在超重/肥胖+GDM与婴幼儿BQ、社交/几何图片注视时间百分比的关系中起着部分中介效应作用；3.ASD儿童早期行为研究发现，ASD高风险儿童显示36月龄前可表现出语言领域发育商CQ、BQ及DQ低于1。本项目为两个RELN单核苷酸多态性及IL-6单核苷酸多态性与ASD风险及症状之间的关联提供了额外的证据，其科学意义为未来有望利用基于基因型的方法检测出ASD高危个体或鉴别不同表型的ASD患者，做到早期干预及精准干预，改善ASD患者预后。本项目结果提示应对计划怀孕的女性进行孕前体重管理，在孕期健康管理中当发现孕妇单一产前逆境发生时，应高度警惕后期关联性强的其他产前逆境同时或后续发生，同时监测及干预孕母系统性炎症，可能有利于子代神经发育，降低子代ASD风险，各级医院儿科医师应依托我国儿童保健三级预防监测网络，对 9、18、24 月龄婴幼儿，在其他发育问题常规筛查同时，常规开展 ASD早期筛查。