ABSTRACT: Preeclampsia (PE), a maternal hypertensive disorder, and intrauterine growth restriction (IUGR), pathologically poor fetal growth, often co-occur and are associated with placental insufficiency (PI). 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 previously identified in PE and IUGR, few studies validated the findings in an independent cohort. This study aims to identify altered DNAm in EOPE, LOPE, and normotensive IUGR, validate these alterations, and use the findings 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), while LOPE and IUGR were compared to term controls (GA >37 weeks). Linear regression identified 1703 differentially methylated (DM) sites (FDR<0.05, ∆β>0.1) in EOPE, 5 in LOPE, and 0 in IUGR. Of the 1703 sites associated with EOPE in the discovery cohort, 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 and had 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. DNA methylation data of the validation cohort can be found at GSE98224.
