Differential DNA Methylation in Placental and Maternal Angiogenic Genes is not Altered in Preeclampsia

Preeclampsia is a pregnancy-associated complex condition associated with inflammation, oxidative stress and angiogenic imbalance. Stress sensitive transcription factors nuclear factor-erythroid 2-like 1 (Nrf1) and nuclear factor-erythroid 2-like 2 (Nrf2) are involved in regulation of angiogenic, inflammatory and oxidative stress pathways. Recent evidence suggests a link between Nrf2 and angiogenic factor balance in preeclampsia though the degree to which maternal and placental DNA methylation contributes to disruption of Nrf pathways among women with preeclampsia is unknown. Our central hypothesis is that distinct patterns of DNA methylation in Nrf pathway and angiogenic genes contribute to altered angiogenic balance in preeclampsia. Prospectively, we collected blood in each of three trimesters of pregnancy, maternal white blood cells in the first trimester of pregnancy and placental tissue at delivery from nulliparous women. We analyzed DNA methylation at individual CpG dinucleotides (Illumina Infinium) in Nrf and angiogenic (VEGFA, VEGFB, VEGC, FLT1, KDR, NRF1, PlGF) genes in maternal peripheral blood cells and placenta and circulating angiogenic factors (Millipore Bioplex) from women who developed preeclampsia and normotensive controls (n=6/group). Differences in average methylation beta scores (change in beta score >0.2 indicated significant gain of methylation; >-0.2 indicated significant loss of methylation) determined significant differences between groups. DNA methylation patterns in Nrf and angiogenic genes in maternal white blood cells and placenta were not significantly different in cases/controls. Among women with preeclampsia, PlGF was significantly lower across pregnancy and sFLT1 was significantly higher in the third trimester among women with preeclampsia. DNA methylation in Nrf and angiogenic genes was not associated with altered angiogenic balance in women who developed late onset preeclampsia. Differences in DNA methylation may occur later in pregnancy when circulating factors differed between groups.