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Fetal Growth associates with Altered Expression of Imprinted Genes in the Placenta

Presented at the Neonatal Society 2013 Summer Meeting (programme).

Piyasena C1,2, B Khulan1, Menon G2, Reynolds R1, Drake AJ1

1 Endocrinology Unit, BHF/Centre for Cardiovascular Science, Queen’s Medical Research Institute, Edinburgh, UK
2 Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, UK

Background: Variability in disease risk is graded across the usual range of birth weight within the population. Altered function of imprinted genes may be one mechanism in the developmental origins of disease. We studied the expression of candidate imprinted genes in the placenta with respect to anthropometric parameters at birth. We also studied cytosine methylation (5mC) and, the newly described, 5-hydroxymethylcytosine (5hmC) at differentially methylated regions (DMRs)

Methods: Placental samples for 63 term singleton infants were obtained from the Edinburgh Reproductive Tissue Bio-Bank. Samples were chosen to represent a wide variation in birth weight (range 2.16 – 4.61kg, median 3.39kg). Pregnancies complicated by congenital abnormalities or diabetes were excluded. Standard deviation scores (SDS) were derived from “British 1990 reference data, reanalysed 2009” (1). Gene expression was analysed using qPCR and geNorm (2) and Normfinder (3) were used to determine a stable reference gene. Enrichment of 5mC was performed using the Active Motif MethylCollector Ultra and enrichment of 5hmC using hydroxymethyl DNA immunoprecipitation. Percentage enrichment of candidate loci was analysed using qPCR.

Results: Insulin-like growth factor 2 (IGF2) expression correlated positively with birthweight SDS when adjusted for maternal BMI and parity (r = 0.301 p = 0.021, adjusted p = 0.03) but not when pre-eclampsia and smoking were added into the regression model (adjusted p = 0.106). In adjusted analyses, p57KIP2 cyclin-dependent kinase inhibitor (CDKN1C) expression correlated negatively with birthweight SDS (r = -0.312, p =0.013, adjusted p = 0.037). In adjusted analyses, 5mC at IGF2 DMR0 correlated with birthweight SDS (r = 0.369, p = 0.002, adjusted p = 0.023) and also at KvDMR, the imprinting control region for CDKN1C, (r = 0.29, p = 0.021, adjusted p = 0.016). There was no association between 5hmC levels at these regions and size at birth.

Conclusion: We present further evidence that the expression of imprinted genes are associated with fetal growth and that this may be mediated through alterations in cytosine methylation at gene regulatory regions. This may bring more insight into the non-Mendelian inheritance of birthweight and the development of adult chronic disease.

1. LMS growth, version 2.71, 2011.

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