The role of imprinted genes in human fetal growth

Identifying the genes important for fetal growth will help to understand common, serious complications of pregnancy such as intrauterine growth restriction (IUGR). Of particular interest are imprinted genes, which show monoallelic, parent-of-origin specific expression. Genes that are paternally derived tend to enhance fetal growth whereas maternally expressed genes suppress growth. A significant correlation between lower birth weight and increased expression of maternally expressed, pleckstrin homology-like domain, family A, member 2 (PHLDA2) in term placenta, without loss of imprinting, had been reported previously. We have identified a novel copy number variant (CNV1) in the PHLDA2 promoter which reduced the promoter efficiency in a luciferase reporter gene assay. Meta-analysis of CNV1 genotype data obtained from three independent white European normal birth cohorts (total n = 9,433) showed that maternal inheritance of CNV1 resulted in a 93 g increase in birth weight (P = 0.01). Moreover, when the mother was homozygous for CNV1, the influence on birth weight was 155 g (P = 0.04), a similar magnitude to the reduction caused by maternal smoking. The expression levels of paternally expressed gene 3 (PEG3), delta-like 1 homolog (DLK1) and maternally expressed gene 3 (MEG3) measured by real-time PCR in >110 normal term placentas from a white European cohort did not show correlation with fetal birth size measurements, except for a trend of positive association observed for DLK1 expression and birth weight (P = 0.072). Paternal inheritance of the type 1 diabetes (T1D) protective G allele of rs941576 SNP located in the DLK1-MEG3 locus was shown to be associated with a 132 g (P = 0.011) and 0.5 cm (P = 0.011) reduction in birth weight and head circumference respectively. This newly described PHLDA2 promoter CNV and rs941576 SNP, alongside their expressions, may provide useful genetic biomarkers/indicators for predicting birth size.