In-utero Exposure and Infant Loss of IGF2 Imprinting

描述（由申请人提供）：IGF2印记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。IGF2印记障碍在人类过度生长障碍贝克威氏综合征患者中也有报道。Wilm肿瘤和肝母细胞瘤患者在IGF2中LOI的发生率更高。在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。尽管吸烟等环境暴露与这些表观遗传改变有关，但其背后的因素尚不清楚。尽管越来越多的证据表明IGF2中的LOI可能发生在子宫内，但这种表观遗传事件的发生时间尚不清楚。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在有丝分裂上是可遗传的，因此有助于IGF2失调固有的有害结果。该研究的具体目的是：1)表征甲基化模式并估计宫内IGF2中LOI的患病率；2)评估母亲吸烟暴露是否与IGF2中的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。该项目招募并储存了来自达勒姆、奥兰治和威克县所有产科护理机构的参与者的脐带血。我们将从项目数据库中前瞻性地识别200名吸烟和200名不吸烟的母亲，并在分娩时获得5ml脐带血，以确定IGF2 DNA甲基化模式和IGF2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。由于由于DMA序列保持不变，随着印迹的恢复，LOI具有潜在的可逆性（除非突变发生在调节甲基化的基因中），确定IGF2 LOI的时间和影响这一表观遗传事件的因素对临床显性慢性疾病的发病率具有广泛的干预前景。这项拟议的研究也有可能为未来调查慢性疾病（包括糖尿病、心血管疾病和某些癌症）病因的研究提供基础。

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.