DNA甲基化动态修饰介导的“早期儿”认知-运动障碍预警评估模式研究

Recently, the definition of “early term children” （birth at 37-38+6 gestational week）has been proposed by American Society of perinatal medicine. The previous studies conducted by our colleagues have shown that the prevalence of cognitive-motor disability in early term children were significantly higher than that of general population. Its symptom can be extended to adulthood with great social threat. The screening and intervention of early children would be neglected when compared with preterm children. There were few studies in this field according to the literature. Based on this situation, we conducted the whole genome DNA methylation test using umbilical cord blood of early term and term children, and compared the different methylated sites between them so as to analyze the biological pathway of the selected Key Gene using samples of periphery blood. Simultaneously, the postpartum follow-up study of China’s Labor Research (2000 early term children were included) was conducted to assess the cognitive-motor ability in less-super early and early period in the development process and family environment, and to analyze the reliability and validity of the related measurements. We also conducted the nested case-control study based on the cohort and analyzed the relationships among ability, gene and environment mediated by dynamic methylation, so that selecting the key biological signals and making the criterion of categories. Moreover, the above results were translated and applied. The early warning and assessment precision model was established according to our results. The objectives of decreasing the prevalence of children with cognitive-motor disability and improving its prognosis will be reached finally.

近期，美国围产医学会确立了“早期儿”（37-38+6孕周出生）的定义，而项目组前期研究显示早期儿认知-运动障碍的患病率明显高于足月儿，症状可延续至成年且社会危害巨大，但较早产儿更易被“忽视”。基于国际上该领域研究甚少的现状，本项目将早期儿和足月儿脐血样本进行全基因组DNA甲基化测试，筛选两组间的差异性位点，分析关键靶基因的相关生物学通路。并采集早期儿各月龄外周血样本，分析关键基因甲基化程度和动态变化趋势。同时，利用中国产程研究产后随访队列(2000例早期儿)，进行“亚超早期”及发育进程中认知-运动功能和家庭环境的评估及量化工具的信效度评价。开展队列为基础的巢式病例-对照研究，分析以甲基化动态修饰为介导的认知-运动功能、基因和环境的相互关系，筛选关键“预警”标志物和分类标准。并将结果转化应用，建立早期儿认知-运动障碍预警评估精准化模式以便达到降低早期儿认知-运动障碍患病率及改善其预后的目的。

背景和目的: 近期，美国围产医学会确立了“早期儿”(37-38+6孕周出生)的定义，而项目组前期研究显示早期儿认知-运动障碍的患病率明显高于足月儿，症状可延续至成年且社会危害巨大，但较早产儿更易被“忽视”。.方法和结果：1)在量化工具应用性评价的基础上，针对早期儿中进行“亚超早期”及发育进程中认知-运动功能的分析，以及家庭支持环境对认知-运动功能的影响。结果显示，Dubowitz神经学测试（亚超早期评估）信度良好并对婴儿期神经行为发育水平具有一定预测价值。发育进程测试（贝利发育评估筛查量表第三版）早期儿的得分均落后于完全足月儿(p<0.001)，精细运动发育迟缓的风险均高于完全足月儿(p<0.05)。对婴儿运动发育家庭环境支持量表开展信效度评价结果显示该量表内部一致性信度和折半信度良好。探索性因素分析提取“活动空间”、“粗大运动玩具”、“精细运动玩具”和“活动多样性”四个因子，显示结构效度良好。并且良好的家庭运动支持环境对各月龄婴儿的认知-运动水平存在促进作用（p<0.05）。2）采用全基因组DNA甲基化测试，进行GO功能和KEGG通路富集分析，并根据通路相关、位点相关、功能表型相关的标准及结合引物预设计结果，共筛选出38个关键基因甲基化位点作为“预警”标志物，并对筛选出的关键位点进行甲位化测序，发现早期儿从出生到1岁的甲基化变化程度（部分）与完全足月儿有显著差异。3）建立婴幼儿认知-运动预警评估模式。以Dubowitz神经学评估(亚超早期)结合筛选的关键甲基化位点作为基线判断标准，确定预警等级界值，将早期儿分为高度风（红色预警），中度风险（橙色预警）、低度风险（黄色预警）和绿色四类人群，制定不同的随访和干预计划，进行分类管理。在随访过程中，采用《婴幼儿家庭运动环境支持量表》和《贝莉婴幼儿发育量表》，对婴幼儿发育过程中可能出现的早期症状和运动支持环境进行动态评估和制定以评估为基础的早期干预策略。.结论和意义：早期儿的认知-运动水平的监测不容忽视，利用项目建立的预警模式进行分类管理，在有限医疗资源前提下实现早期儿有效的早期预防和干预。.成果：项目在SCI索引和核心期刊杂志发表SCI或统计源期刊论文共26篇（负责人为第一或通讯作者）。