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

胎儿酒精影响儿童的鉴定：印记基因表达和甲基化的改变作为神经行为和生长障碍的生物标志物。

• 批准号: 10529064
• 负责人: ROBERT COLIN CARTER
• 金额: $ 5.98万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10529064
• 关键词: Adolescent; Adverse effects; Affect; Age; Alcohol consumption; Alcohol-Related Neurodevelopmental Disorder; Alcohols; Animal Model; Area; Behavior; Behavioral; Biological Markers; Blood; Blood specimen; Child; Childhood; Cognitive; Color; Communities; Data; Development; Diagnosis; Diagnostic; Dysmorphology; Epigenetic Process; Experimental Animal Model; Face; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Gene Cluster; Gene Expression; Genes; Genomic Imprinting; Growth; Growth Disorders; Impairment; Individual; Infant; Intervention; Learning; Literature; Longitudinal cohort; Machine Learning; Malnutrition; Maps; Mediating; Memory; Methylation; Microcephaly; Neurocognitive Deficit; Neurodevelopmental Disability; Neurodevelopmental Impairment; Nursery Schools; Parents; Pattern; Placenta; Play; Pregnancy; Prevalence; Public Health; Role; Sampling; South Africa; Systems Biology; Techniques; Testing; Therapeutic Intervention; Tissues; Toxin; alcohol effect; base; clinical practice; cohort; diagnostic tool; early childhood; fetal; fetal diagnosis; gene function; imprint; infancy; neurobehavioral; novel; performance tests; postnatal; prenatal; prospective; public health relevance; recruit; targeted treatment; trait; transcriptome; whole genome

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.

抽象的 胎儿酒精谱系（FASD）是神经发育的最常见预防原因 残疾人，美国的患病率估计为3-10/1000人，最高80/1000 社区。量身定制为产前酒精暴露的干预措施越来越多的承诺 （PAE）与临床实践中的诊断困难受到限制相关的神经性缺陷。目前已知 暴露的生物标志物既不敏感也不针对神经行为缺陷，部分原因是不是全部 暴露的儿童受到影响。因此，有生物标志物的迫切需要识别 受影响的儿童，他们将从早期，量身定制的治疗干预措施中受益。越来越多的身体 文献表明，酒精引起的表观遗传程序的改变是重要的潜力 FASD中的机制，表明这种改变可能是效果的生物标志物。印迹基因 包括对产前侮辱敏感的表观遗传调节基因的独特子集。有 受FASD影响的神经行为结构域与实验中看到的神经行为结构域之间存在相当大的重叠 印迹基因失调的动物模型，包括学习，记忆和依恋。在产前 - 招募，前瞻性纵向队列，我们​​最近发现PAE与改变有关 93个表达的11个表达的胎盘表达水平。其中五个的表达变化 基因统计介导的酒精对产后生长的影响，将这些改变鉴定为生物标志物 胎儿酒精生长限制。考虑到受影响的神经行为域之间的显着重叠 在FASD和受动物模型中印迹基因表达影响的那些中，酒精诱导的 胎盘印迹基因表达的改变也可能为FASD神经认知提供生物标志物 缺陷。尽管大多数表观遗传标记是针对组织类型和暴露时间的特异性标记，但基因组印记 地图和我们的试验数据表明，在胎盘组织中鉴定出的印迹基因失调的标记可能 在年龄较大的血液样本中检测到。这项研究的目的是：（1）表征 胎盘中与胎儿酒精相关的不合理签名和在6年时获得的血液样本中； （2）至 确定可以用作印迹基因表达水平和ICR甲基化水平的变化 生物标志物； （3）从第二独立的血液样本中验证目标1和2中的发现 队列。这项研究的数据将来自从开普敦招募的两个前瞻性纵向人群 南非开普敦的有色社区，FASD的流行率是 世界。这项研究的结果将使您可以识别受益的儿童 当前的诊断工具可能无法检测到早期的治疗干预措施，但可能不会检测到。