Introduction Preeclampsia (PE) carries increased risks of cardiovascular- and metabolic diseases in mothers and offspring during the life course. While the severe early-onset PE (EOPE) phenotype originates from impaired placentation in early pregnancy, late-onset PE (LOPE) is in particular associated with pre-existing maternal cardiovascular- and metabolic risk factors. We hypothesize that PE is associated with altered epigenetic programming of placental and fetal tissues and that these epigenetic changes might elucidate the increased cardiovascular- and metabolic disease susceptibility in PE offspring. Methods A nested case-control study was conducted in The Rotterdam Periconceptional Cohort comprising 13 EOPE, 16 LOPE, and three control groups of 36 uncomplicated pregnancies, 27 normotensive fetal growth restricted and 20 normotensive preterm birth (PTB) complicated pregnancies. Placental tissue, newborn umbilical cord white blood cells (UC-WBC) and umbilical vein endothelial cells were collected and DNA methylation of cytosine-guanine dinucleotides was measured by the Illumina HumanMethylation450K BeadChip. An epigenome-wide analysis was performed by using multiple linear regression models. Results Epigenome-wide tissue-specific analysis between EOPE and PTB controls revealed 5001 mostly hypermethylated differentially methylated positions (DMPs) in UC-WBC and 869 mostly hypomethylated DMPs in placental tissue, situated in or close to genes associated with cardiovascular-metabolic developmental pathways. Discussion This study shows differential methylation in UC-WBC and placental tissue in EOPE as compared to PTB, identifying DMPs that are associated with cardiovascular system pathways. Future studies should examine these loci and pathways in more detail to elucidate the associations between prenatal PE exposure and the cardiovascular disease risk in offspring.

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Keywords Cardiovascular disease, DNA methylation, Fetal programming, HUVEC, Illumina HumanMethylation450K BeadChip, Umbilical cord white blood cells
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Journal Placenta
Grant This work was funded by the European Commission 7th Framework Programme; grant id h2020/633595 - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging (DYNAHEALTH), This work was funded by the European Commission 7th Framework Programme; grant id h2020/733206 - Early-life stressors and LifeCycle health (LIFECYCLE)
Herzog, E, Eggink, A.J, Willemsen, S.P, Slieker, R, Wijnands, K.P.J, Felix, J.F, … Steegers-Theunissen, R.P.M. (2017). Early- and late-onset preeclampsia and the tissue-specific epigenome of the placenta and newborn. Placenta, 58, 122–132. doi:10.1016/j.placenta.2017.08.070