Hypertensive disorders of pregnancy share common cfDNA methylation profiles

Hypertensive disorders of pregnancy (HDP) contribute substantially to perinatal morbidity and mortality. Epigenetic changes point towards cardio-metabolic dysregulation for these vascular disorders. In early pregnancy, epigenetic changes using cell free DNA (cfDNA) are largely unexplored. We aimed to investigate these in HDP between 11 and 14 weeks of gestation by analysis of cfDNA methylation profiles in patients with hypertensive disorders. We identified patients without chronic hypertension but with subsequent development of preeclampsia (PE) (n = 11), with chronic hypertension (HT) but without PE development (n = 14), and lacking both PE and HT (n = 422). We matched patients according to PE risk factors into three groups (n = 5 each group): (1) PE: no HT but PE development, (2) HT: chronic hypertension but no PE and (3) Control: no PE or HT. We successfully optimized our cfDNA isolation process prior to whole genome bisulfite sequencing. Analysis of cfDNA methylation changes indicate a common predisposition in PE and HT groups, chiefly of maternal origin. Assessment of significant differentially methylated regions and annotated genes point towards a common cardiovascular predisposition in preeclampsia and hypertension groups in the first trimester. We postulate the pivotal role of the maternal cardiovascular system in HDP, which is already evident in the first trimester.