In-utero Exposure and Infant Loss of IGF2 Imprinting

描述（申请人提供）：IGF 2印迹缺失已在广泛的成人慢性疾病中发现，包括糖尿病、心血管疾病和恶性肿瘤。IGF 2印记障碍也在人类过度生长障碍Beckwith-Wiedemann综合征患者中报告。肾母细胞瘤和肝母细胞瘤患者IGF 2的LOI患病率较高。在结肠癌和白血病患者的淋巴细胞中，也有报道IGF 2外显子3和9上差异甲基化区域的甲基化改变。这些表观遗传改变的潜在因素尚不清楚，尽管吸烟等环境暴露与此有关。这种表观遗传事件的时间也是未知的，尽管越来越多的证据表明IGF 2中的LOI可能发生在子宫内。我们假设IGF 2中的LOI部分是对IGF 2中异常甲基化变化的反应，并且因为这些甲基化模式是有丝分裂可遗传的，导致IGF 2失调中固有的有害结果。该研究的具体目的是：1）描述甲基化模式并估计宫内IGF 2中LOI的患病率; 2）评估母亲吸烟是否与IGF 2中LOI相关; 3）评估IGF 2中LOI是否与出生后第一年婴儿体重快速增加相关，这是吸烟母亲婴儿的特征。拟议的研究建立在脐带血移植（COBLT）项目的现有数据收集结构的基础上。该项目从达勒姆、橙子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确定200名吸烟母亲和200名非吸烟母亲，并在分娩时获得多达5 ml的脐带血，以确定IGF 2 DNA甲基化模式和IGF 2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。因为LOI是潜在可逆的，因为DMA序列保持不变，（除非突变是在基因调控甲基化），识别IGF 2 LOI的时间和影响这种表观遗传事件的因素，具有广泛的干预前景，在临床上明显的慢性疾病发病率的印记恢复。这项拟议的研究也有可能为未来调查慢性疾病病因的研究提供基础，包括糖尿病，心血管疾病和一些癌症。

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.