In-Utero Exposures and Deregulation of IGF2

Loss of Imprinting in IGF2 has been found in a wide spectrum of adult chronic diseases including 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. ExpandCollapse Abstract