70: Epigenetic orchestration of circulating insulin-like growth factor-2 levels in cord blood

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Genetics/Ultrasound

70 Epigenetic orchestration of circulating insulin-like growth factor-2 levels in cord blood Kimberly Fortner1, Amy Murtha1, Cathrine Hoyo2, Francine Overcash2, Zhiquing Huang3, Joellen Schildkraut2, Joanne Kurtzberg4, Randy Jirtle5, Michele Forman6, Susan Murphy3 1

Duke University, Division of Meternal Fetal Medicine, Dept OB/Gyn, Durham, North Carolina, 2Duke University, Department of Community and Family Medicine, Durham, North Carolina, 3Duke University, Division Gynecologic Oncology, Dept OB/Gyn, Durham, North Carolina, 4 Duke University, Pediatric Blood/Marrow Transplantation, Department of Pathology, Durham, North Carolina, 5Duke University, Department of Radiation Oncology, Durham, North Carolina, 6UT MD Anderson Cancer Center, Department of Epidemiology, Houston, Texas

OBJECTIVE: Perturbations in epigenetic reprogramming may increase susceptibility to disease, particularly for growth-regulatory imprinted genes. Altered methylation in Differentially Methylated Regions (DMRs) controlling Insulin-like Growth Factor 2 (IGF2) imprinting leads to increased transcription and presumably altered IGF2 levels (associated with chronic diseases). The link between IGF2 DMR methylation and IGF2 protein levels is not established. Our objective was to determine the relationship between IGF2 DMR methylation and circulating levels of IGF2 at birth. STUDY DESIGN: Of the 601 subjects enrolled in this prospective cohort study (2005-09), 590 were followed to delivery (98.2%). These anal-

Oral Concurrent Session 6

yses include 290 participants with complete methylation and protein data. Genomic cord blood DNA was evaluated for methylation by Pyrosequencing at loci: IGF2 DMR0 and H19 CBS1. Cord plasma IGF2 levels were measured using ELISA (DSL Inc, Texas). Using generalized linear models, the relationships between methylation at each DMR and IGF2 levels were evaluated. RESULTS: IGF2 levels did not vary by maternal age, insurance status, obesity, smoking, gestational age or birthweight. Mean IGF2 levels were higher in non-black compared to black infants (1124 vs. 965 ng/ml, p⫽0.01) as well as vaginal compared to cesarean delivery (1081 vs. 937 ng/ml, p⫽0.01). After adjusting for these factors, we found a strong inverse linear association between methylation fraction at IGF2 DMR0 and protein levels (p⫽0.02). This association was apparent in infants born to mothers with BMI⬎30kg/m2 (p⫽0.001) as well as mothers who smoke (p⫽0.06). CONCLUSION: Altered methylation at H19 CBS1 and IGF2 DMR0 was associated with decreased IGF2 protein levels in cord blood. This is the first study demonstrating DMR methylation established in utero is associated with circulating IGF2 levels. This association, independent of race and delivery route, suggests that altered methylation in infants of obese mothers may be predictive of sustained changes in IGF2 protein levels and consequent risk of developing disease. 0002-9378/$ – see front matter • doi:10.1016/j.ajog.2009.10.085

Supplement to DECEMBER 2009 American Journal of Obstetrics & Gynecology

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