The value of DNA methylation profiling in characterizing preeclampsia and intrauterine growth restriction

Placental health is a key component to healthy pregnancy. Placental insufficiency (PI), inadequate nutrient delivery to the fetus, is associated with preeclampsia (PE), a maternal hypertensive disorder, and intrauterine growth restriction (IUGR), pathologically poor fetal growth. PI is more common in early-onset PE (EOPE) than late-onset PE (LOPE). However, the relationship between these disorders remains unclear. While DNA methylation (DNAm) alterations have been identified in PE and IUGR, these entities can overlap and few studies have analyzed these separately. This study aims to identify altered DNAm in EOPE, LOPE, and normotensive IUGR, validate these alterations, and use them to better understand the relationships between these related disorders. Placental samples from a discovery cohort (43 controls, 22 EOPE, 18 LOPE, 11 IUGR) and validation cohort (15 controls, 22 EOPE, 11 LOPE) were evaluated using the Illumina HumanMethylation450 array. To minimize gestational age (GA) effects, EOPE samples were compared to pre-term controls (GA 37 weeks). There were 1703 differentially methylated (DM) sites (FDR0.1) in EOPE, 5 in LOPE, and 0 in IUGR. Of the 1703 EOPE sites, 599 were validated in the second cohort. These sites cluster samples from both cohorts into 3 distinct methylation clusters. Interestingly, LOPE samples diagnosed between 34-36 weeks with co-occurring IUGR clustered with the EOPE methylation cluster. DNAm profiling may provide an independent tool to refine clinical diagnoses into subgroups with more uniform pathology. The challenges in reproducing genome-wide DNAm studies are also discussed.