DNA Methylation in Candidate Genes as a Biomarker for Transgenerational Risk of Preeclampsia

Preeclampsia (PE), characterized by global fetal undernutrition due to placental insufficiency, affects over 100,000 women annually in the US. Gene-environment interactions resulting from placental insufficiency during critical developmental windows may explain differential methylation of key genes associated with familial risk of PE. In this study, our goal was to validate methylation status of CpG dinucleotides in loci of genes identified via genome-wide methylation array (Illumina Infinium) in women with and without PE (n=6/group). Differentially methylated loci were primarily located in non-CpG island regions of genes. Bisulfite sequencing was performed on maternal peripheral blood samples and placental tissue of fetal origin to detect methylated cytosines in 7 candidate genes involved with vascular function, inflammation, and lipid metabolism. Pyrosequencing was performed to identify conversion of unmethylated cytosine to uracil in the altered sequence, providing single-nucleotide resolution of the segment of DNA. This study provides novel evidence for the generation of epigenomic marks associated with an intrauterine environment of placental insufficiency, providing a putative explanation for the heritable risk of preeclampsia across generations.