DNA methylation profiles of genes associated with angiogenesis in the samples of placenta in pregnancies complicated by intrauterine growth restriction.

BACKGROUND: Impairment in placental angiogenesis is blamed for the etiopathogenesis of intrauterine growth restriction (IUGR). AIM: To assess the genes related to angiogenesis in placental biopsies of pregnancies complicated by IUGR that could be aberrantly methylated and adversely affect placental angiogenesis. METHODS: The methylation profiles of soluble fms-like tyrosine kinase-1 (sFLT-1), vascular endothelial growth factor (VEGF), and the placental growth factor (PIGF) were evaluated using Illumina MiSeq™ System in placental biopsies from term IUGR pregnancies without preeclampsia (n = 18) and healthy controls (n = 17). DNA was isolated from samples of tissue collected from the fetal side of the placenta. In the targeted regions, we have identified 30, 24, and 29 CpG islands (CpGi) within sFLT-1, VEGF and PIGF genes, respectively. CpGi which are most methylated in the promoter regions of three genes were selected for the study from the database http://www.ensembl.org. RESULT(S): IUGR fetuses had significantly lower placental and fetal birth weight than controls. The promoter of sFLT-1 at three CpGi and VEGF at six CpGi were the regions with significant methylation differences between IUGR and control placentas. sFLT-1 was hypermethylated at 265 and 352 CpGi; however, hypermethylation was lower in IUGR group compared to control group at this position. sFLT-1 was hypomethylated at 456 CpGi in IUGR group and hypermethylated at the same region in control group. VEGF was hypomethylated at 668, 703, and 710 CpGi in control and IUGR groups; however, hypomethylation at these positions was significantly higher in control group compared to IUGR. 776, 845, and 863 CpGi of VEGF promoter were significantly hypermethylated in IUGR group whereas hypomethylated in control group. The methylation profile of PIGF did not differ between the groups. After adjustment for the factors known to affect fetal birth weight, DNA methylation of VEGF 668 CpGi had a significant negative association with fetal birth weight in the control and the IUGR group and a positive association with IUGR pregnancies. CONCLUSION(S): Our results do not support the hypothesis that altered DNA methylation in the placental angiogenic genes is a major mechanism generally involved in IUGR. Only a specific region (at 668 CpGi) corresponding to the promoter of VEGF may serve as an epigenetic marker of IUGR and may be involved in the mechanism of IUGR. Large sample-sized studies are needed to understand the effects of DNA methylation on placental gene function and how they might influence fetal growth.

Increased pancreatic-derived factor (PANDER) levels in gestational diabetes mellitus.

The aim of the study was to investigate the pancreatic-derived factor (PANDER) levels in healthy pregnant women and in pregnant women with gestational diabetes mellitus (GDM). A total of 50 women consecutively diagnosed with GDM and 30 randomly selected age-matched and gestational-age-matched healthy pregnant women were included in this cross-sectional study. Serum PANDER levels and other variables were analyzed. The age, the gestational age at the time, the blood sample was obtained and the hemoglobin A1c (HbA1c) levels of the GDM and control groups were similar. The body mass index (BMI), fasting blood glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and serum PANDER levels were significantly higher in the GDM group than the control group. The optimal PANDER cutoff value was 227.2 ng/ml, and the ratios above this value were 100 and 86.6% for sensitivity and specificity, respectively (p=.0001). Serum PANDER levels were higher in women with GDM compared to the control group and were positively correlated with insulin, HOMA-IR, and HbA1c levels. These results suggest that PANDER might be considered a new biomarker for GDM.