In-utero Exposure and Infant Loss of IGF2 Imprinting

子宫内暴露和婴儿 IGF2 印记丧失

• 批准号: 7145764
• 负责人: Cathrine Hoyo
• 金额: $ 19.45万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145764
• 关键词: DNA methylation; cell cycle; clinical research; cord blood; embryo /fetus toxicology; environmental exposure; environmental toxicology; epidemiology; epigenetics; gene environment interaction; gene expression; genomic imprinting; human subject; infant human (0-1 year); insulinlike growth factor; molecular pathology; passive smoking; patient oriented research; smoking; tobacco abuse; weight gain

DESCRIPTION (provided by applicant): Loss of Imprinting in IGF2 has been found in a wide spectrum of adult chronic diseases jncluding diabetes, cardiovascular diseases and malignancies. IGF2 imprint disorders have also been reported in patients with the human overgrowth disorder Beckwith-Wiedemann syndrome. Patients with Wilm's tumor and hepatoblastoma have a higher prevalence of LOI in IGF2. Methylation changes of differentially methylated regions on exon 3 and 9 of IGF2 have also been reported in lymphocytes of patients with colon cancer and leukemia. Factors underlying these epigenetic alterations are unknown, although environmental exposures such as cigarette smoking have been implicated. The timing of this epigenetic event is also unknown, although accumulating evidence suggests that LOI in IGF2 may occur in-utero. We hypothesize that LOI in IGF2 is a response, in part, to aberrant methylation changes in IGF2, and because these methylation patterns are mitotically heritable, contributes to deleterious outcomes inherent in IGF2 deregulation. The specific aims of the study are: 1) To characterize methylation patterns and estimate the prevalence of LOI in IGF2 in-utero; 2) To evaluate whether maternal exposure to cigarette smoking is associated with LOI in IGF2; and 3) To evaluate whether LOI in IGF2 is associated with rapid infant weight gain during the first year of life, characteristic of infants of smoking mothers. The proposed research builds on an existing data collection structure of the Cord Blood Transplantation (COBLT) Project. This project recruits and stores cord blood of participants from all Obstetrics Care facilities in Durham, Orange and Wake Counties. We will prospectively identify 200 smoking and 200 non-smoking mothers from the Project database and obtain up to 5ml of cord blood at delivery to determine IGF2 DNA methylation patterns and biallelic expression of IGF2. We will then examine these patterns according to maternal smoking status and infant weight gain. Because LOI is potentially reversible with imprinting restored since the DMA sequence remains unaltered, (unless mutation is in genes regulating methylation) identifying the timing of IGF2 LOI and factors influencing this epigenetic event has wide ranging intervention prospects on clinically apparent chronic disease incidence. The proposed study also has the potential to provide a foundation for future studies investigating the etiology of chronic diseases, including diabetes, cardiovascular diseases and some cancers.

描述（由申请人提供）：IGF2 印记丢失已在多种成人慢性疾病中发现，包括糖尿病、心血管疾病和恶性肿瘤。人类过度生长障碍 Beckwith-Wiedemann 综合征患者中也有 IGF2 印记障碍的报道。肾母细胞瘤和肝母细胞瘤患者的 IGF2 LOI 患病率较高。结肠癌和白血病患者的淋巴细胞中也报道了 IGF2 外显子 3 和 9 上差异甲基化区域的甲基化变化。这些表观遗传改变背后的因素尚不清楚，尽管吸烟等环境暴露与此有关。尽管越来越多的证据表明 IGF2 中的 LOI 可能在子宫内发生，但这种表观遗传事件的发生时间也是未知的。我们假设 IGF2 中的 LOI 部分是对 IGF2 异常甲基化变化的反应，并且由于这些甲基化模式是有丝分裂遗传的，因此会导致 IGF2 失调所固有的有害结果。该研究的具体目的是： 1) 表征甲基化模式并估计子宫内 IGF2 中 LOI 的流行率； 2) 评估母亲吸烟暴露是否与IGF2的LOI相关； 3) 评估 IGF2 中的 LOI 是否与婴儿出生后第一年体重快速增加有关，这是吸烟母亲的婴儿的特征。拟议的研究建立在脐带血移植（COBLT）项目现有数据收集结构的基础上。该项目从达勒姆县、奥兰治县和威克县的所有产科护理机构招募并储存参与者的脐带血。我们将从项目数据库中前瞻性地识别 200 名吸烟母亲和 200 名不吸烟母亲，并在分娩时获取最多 5ml 的脐带血，以确定 IGF2 DNA 甲基化模式和 IGF2 的双等位基因表达。然后，我们将根据母亲吸烟状况和婴儿体重增加来检查这些模式。由于 DMA 序列保持不变，随着印记恢复，LOI 可能是可逆的（除非调节甲基化的基因发生突变），识别 IGF2 LOI 的时间和影响这一表观遗传事件的因素对于临床明显的慢性病发病率具有广泛的干预前景。拟议的研究还有可能为未来调查慢性疾病（包括糖尿病、心血管疾病和一些癌症）病因学的研究奠定基础。