Systematic review supports the role of DNA methylation in the pathophysiology of preeclampsia: a call for analytical and methodological standardization

Abstract

Background Studies have recently examined the role of epigenetic mechanisms in preeclampsia pathophysiology. One commonly examined epigenetic process is DNA methylation. This heritable epigenetic marker is involved in many important cellular functions. The aim of this study was to establish the association between DNA methylation and preeclampsia and to critically appraise the roles of major study characteristics that can significantly impact the association between DNA methylation and preeclampsia. Main body A systematic review was performed by searching PubMed, Web of Science, and EMBASE for original research articles published over time, until May 31, 2019 in English. Eligible studies compared DNA methylation levels in pregnant women with vs. without preeclampsia. Ninety articles were included. Epigenome-wide studies identified hundreds of differentially methylated places/regions in preeclamptic patients. Hypomethylation was the predominant finding in studies analyzing placental tissue (14/19), while hypermethylation was detected in three studies that analyzed maternal white blood cells (3/3). In candidate gene studies, methylation alterations for a number of genes were found to be associated with preeclampsia. A greater number of differentially methylated genes was found when analyzing more severe preeclampsia (70/82), compared to studies analyzing less severe preeclampsia vs. controls (13/27). A high degree of heterogeneity existed among the studies in terms of methodological study characteristics including design (study design, definition of preeclampsia, control group, sample size, confounders), implementation (biological sample, DNA methylation method, purification of DNA extraction, and validation of methylation), analysis (analytical method, batch effect, genotyping, and gene expression), and data presentation (methylation quantification measure, measure of variability, reporting). Based on the results of this review, we provide recommendations for study design and analytical approach for further studies. Conclusions The findings from this review support the role of DNA methylation in the pathophysiology of preeclampsia. Establishing field-wide methodological and analytical standards may increase value and reduce waste, allowing researchers to gain additional insights into the role of DNA methylation in the pathophysiology of preeclampsia.

A cross-cohort analysis of autosomal DNA methylation sex differences in the term placenta

“…Epigenome-wide association studies have been conducted to investigate the effects of disease and exposures in pregnancy, generally focusing on autosomal variation. Disease-related EWAS of the placenta include preeclampsia [ 17 – 21 ] (reviewed in [ 22 ]), acute chorioamnionitis [ 23 ], intrauterine growth restriction [ 20 , 24 ], and fetal birthweight [ 25 ], among others. Recent placental EWAS of environmental exposures and maternal phenotypes include investigations into heavy metals [ 26 , 27 ], pollution [ 28 , 29 ], maternal smoking [ 30 ], maternal stress [ 31 ], blood pressure [ 32 ], diabetes [ 33 ], body mass index, gestational weight gain, and dyslipidemia [ 34 , 35 ].…”

Methylome-wide analysis of IVF neonates that underwent embryo culture in different media revealed no significant differences

“…Alternatively, differential variability at certain CpG sites could be driven by factors that are only experienced by a few individuals in the study population, such as pregnancy complications. Previously, DNA methylation differences associated with pre-eclampsia 50 and gestational diabetes 51 – 53 have been described when analysing UCB samples of neonates. According to our findings, there might be an association between culture medium, the number of differentially variable sites and pregnancy complications, but the design of this study does not allow to discuss the direction of causality (culture media, methylation and pregnancy complications).…”

Early Pregnancy Exposure to Ambient Air Pollution among Late-Onset Preeclamptic Cases Is Associated with Placental DNA Hypomethylation of Specific Genes and Slower Placental Maturation

“…Environmental exposures occurring at this critical period have a potential to induce additional epigenetic changes and alter gene expression, resulting in increased susceptibility to disease [21,22]. In previous studies, altered DNA methylation in PE placentas has been seen, which was presumed to be associated with placental development and function [23]. In addition, a differential DNA methylation placental profile has been found in relation to exposure to ambient air pollution during pregnancy [24].…”