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.

摘要