Identification of fetal alcohol-affected children: Alterations in imprinted gene expression and methylation as biomarkers of neurobehavioral and growth impairment.

摘要 胎儿酒精谱系障碍(FASD)是神经发育最常见的可预防原因 残疾，美国的患病率估计为3-10/1000人，地方性疾病高达80/1000人 社区。承诺为产前酒精暴露量身定做越来越多的干预措施 (PAE)相关的神经行为缺陷在临床实践中受到诊断困难的限制。目前已知 暴露的生物标志物对神经行为缺陷既不敏感也不特异，部分原因是并不是所有的 暴露在空气中的儿童会受到影响。因此，迫切需要有效的生物标志物来识别 将从早期的、量身定制的治疗干预中受益的受影响儿童。不断增长的 文献表明，酒精诱导的表观遗传编程改变是一种重要的潜在因素 FASD的作用机制，提示这种改变可能作为影响的生物标志物。印记基因 包括对产前侮辱敏感的表观遗传调控基因的独特子集。的确有 受FASD影响的神经行为领域与实验中所见的神经行为领域有相当大的重叠 印记基因失调的动物模型，包括学习、记忆和依恋。在产前- 招募的前瞻性纵向队列，我们最近发现PAE与 胎盘表达水平93个印记基因中有11个表达。其中五个的表情发生了变化 基因统计调节酒精对出生后生长的影响，将这些变化识别为生物标记物 胎儿酒精生长受限。考虑到受影响的神经行为领域之间的显著重叠 在酒精诱导的FASD和受印记基因表达改变影响的动物模型中 胎盘印记基因表达的改变也可能为FASD神经认知提供生物标志物 赤字。尽管大多数表观遗传标记是特定于组织类型和暴露时间的，但基因组印记 图谱和我们的试点数据表明，在胎盘组织中发现的印记基因失调的标记可能 在年龄较大的人采集的血液样本中检测到。这项研究的目的是：(1)表征 胎盘和6岁时采集的血液样本中与胎儿酒精相关的印迹组特征； 确定印记基因表达水平和ICR甲基化的变化可以作为 作用的生物标志物；(3)在第二个独立的血液样本中验证AIMS 1和2中的发现 一群人。这项研究的数据将来自从CAPE招募的两个前瞻性纵向队列 南非开普敦的有色人种社区，那里的FASD患病率是世界上最高的之一 世界。这项研究的结果将使确定哪些受影响的儿童将受益于 早期治疗干预，但很可能不会被目前的诊断工具发现。

Abstract Fetal alcohol spectrum disorders (FASD) are the most common preventable cause of neurodevelopmental disabilities, with prevalence estimates of 3-10/1000 individuals in the US and up to 80/1000 in endemic communities. The promise of an increasing number of interventions tailored to prenatal alcohol exposure (PAE)-related neurobehavioral deficits is limited by diagnostic difficulties in clinical practice. Currently known biomarkers of exposure are neither sensitive nor specific for neurobehavioral deficits, in part because not all exposed children are affected. There is, therefore, a critical need for biomarkers of effect to identify affected children who would benefit from early, tailored therapeutic interventions. A growing body of literature has demonstrated alcohol-induced alterations in epigenetic programming as an important potential mechanism in FASD, suggesting that such alterations may serve as biomarkers of effect. Imprinted genes comprise a unique subset of epigenetically regulated genes that is sensitive to prenatal insults. There is considerable overlap between the neurobehavioral domains affected by FASD and those seen in experimental animal models of imprinted gene dysregulation, including learning, memory, and attachment. In a prenatally- recruited, prospective longitudinal cohort, we recently found that PAE was associated with alterations in placental level of expression of 11 of 93 expressed imprinted genes. Expression changes for five of these genes statistically mediated effects of alcohol on postnatal growth, identifying these alterations as biomarkers of fetal alcohol growth restriction. Given the remarkable overlap between the neurobehavioral domains affected in FASD and those affected by alteration of imprinted gene expression in animal models, alcohol-induced alterations in placental imprinted gene expression may also provide biomarkers for FASD neurocognitive deficits. Although most epigenetic marks are specific to tissue-type and timing of exposure, genomic imprinting maps and our pilot data indicate that markers of imprinted gene dysregulation identified in placental tissue may be detected in blood samples obtained at older ages. The aims of this study are: (1) To characterize the fetal alcohol-related imprintome signature in the placenta and in blood samples obtained at 6 yr; (2) To identify alterations in imprinted gene level of expression and ICR methylation that can serve as biomarkers of effect; (3) To validate findings in Aims 1 and 2 in blood samples from a 2nd, independent cohort. The data for this study will come from two prospective longitudinal cohorts recruited from the Cape Coloured community in Cape Town, South Africa, where the prevalence of FASD is among the highest in the world. Results from this study will make it possible to identify affected children who would benefit from early therapeutic interventions but would likely not be detected by current diagnostic tools.