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Table 1 Differentially methylated sites in epigenome-wide studies

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

Ref. no Study Method Major findings
[17] Bourque 2010 IlluminaGoldenGateMethylation Cancer Panel 1 array No significant methylation differences—placenta
[28] Yuen 2010 IlluminaGoldenGateMethylation Cancer Panel 1 192 loci differentially methylated (hypo) in the placenta in EOPE, none in LOPE.
[30] Jia 2012 NimbleGen 385K 102 genes in total showed significant hypermethylation in the promoter-associated CpG islands in severe PE placenta tissue samples, while 194 genes showed significant hypomethylation.
[31] Mousa 2012a HM 27K Not reported
[32] Mousa 2012b HM 27K Not reported
[33] Mousa 2012c HM 27K 4184 CpG sites (3736 genes) differentially methylated when comparing normal pregnant and preeclamptic omental arteries.
[34] Blair 2013 HM 450K 38840 CpG sites with significant differences (282 with > 12.5% difference) in EOPE in the placenta. The majority (74.5%) of these sites were hypomethylated in EOPE.
[35] Hogg 2013a HM 450K Not reported
[18] White 2013 HM 27K PE was associated with widespread differential methylation favoring hypermethylation in maternal peripheral blood (buffy coat). 729 CpGs were hypermethylated, while 268 were hypomethylated in PE, compared to controls.
[36] Anderson 2015 HM 450K Significant differences in DNA methylation were identified in 207 individual CpG sites in WBC, 64% showed a gain, while 36% were associated with a loss of methylation. The majority of the hypermethylated sites in the WBC also showed varying amounts of methylation gain in the placenta tissue, with many sites showing significant methylation gains in the placenta. Also, the hypomethylated sites in WBC were likely to show a loss of methylation to varying degrees in placental tissue, with many sites showing significant methylation losses.
[37] Anton 2014 HM 450K 3411 gene probes (3132 hypermethylated and 279 hypomethylated) were differentially methylated between control and preterm PE (< 37 gestational weeks) placentas. A total of 179 gene probes (164 hypermethylated and 15 hypomethylated) were differentially methylated between term PE (≥ 37 gestational weeks) and preterm PE placentas.
[38] Chu 2014 Infinium microarray (EpityperMassARRAY) 49 CpGs significantly altered in EOPE placental tissue compared to normal controls (after excluding X chromosome-specific probes). Seventy-eight percent were hypomethylated in EOPE. Fewer differentially methylated CpGs were also identified when comparing LOPE with controls. Only a single CpG site, MC1R, was found to be differentially methylated between EOPE and LOPE.
[39] Liu 2014 Methylated-CpG island recovery assay (MIRA) 8191 (2140 genes) differentially methylated regions were identified in PE placentas compared with controls
[40] Blair 2014 HM 450K Not reported
[41] Ching 2014 HM 450K Of 385,184 useful loci for differential methylation analysis, 9995 showed DM (2.6%) between EOPE and control placentas. 91.9% of those DMs (9186 of 9995) were hypermethylated.
[42] Anderson 2014 NimbleGen Not reported
[43] Ching 2015 HM 450K Hypomethylation pattern in EOPE in umbilical cord blood with 51,486 hypomethylated CPG sites and 12,563 hypermethylated sites.
[44] Martin 2015 HM 450K There were 989 DMPs between the preeclamptic and normotensive placentas. Most (80.7%) of the DMPs were hypomethylated in the preeclamptic placentas versus the normotensive placentas, while only 19.3% were hypermethylated.
[45] Zhu 2015 [h]MeDIP with MeDIP-seq A total of 714 differential 5mC peaks (DMRs) were found showing significant differences between late-onset severe PE and controls. Four hundred eighty-seven (68.2%) had higher 5mC levels in the late-onset preeclamptic placentas.
[46] Xuan 2016 NimbleGen 1664 promoters with altered DNA methylation, including 663 hypermethylated and 1001 hypomethylated in placental samples.
[47] Kim 2016 HM 450K Maternal peripheral blood showed 71 differentially methylated CpG loci (44 hypermethylated and 27 hypomethylated), while the placenta revealed 365 loci (37 hypermethylated and 328 hypomethylated).
[48] Wilson 2016 HM 450K Not reported
[49] Suzuki 2016 HELP tagging 123, 85, and 99 loci with high-confidence hypertension-associated, proteinuria-associated, and hypertension- and proteinuria-associated DNA methylation changes in the placenta
[14] White 2016 HM 27K Of 73 analyzed CpGs, 6 genes were differentially methylated in PE buffy coat compared to controls
[50] Yeung 2016 HM 450K A total of 303 differentially methylated regions after adjustment for gestational age (214 hypermethylated and 89 hypomethylated) between preeclampsia cases and controls in the placenta
[51] Herzog 2017 HM 450K 5001 mostly hypermethylated DMPs in the umbilical cord (UC)-WBC and 869 mostly hypomethylated DMPs in placental samples. The methylation levels in EOPE UC-WBCs clearly deviated from those in all other groups. In the comparison of EOPE and PTB, we found 12040 (28%) differentially methylated CpGs in UC-WBC and 5668 (0.5%) differentially methylated CpGs in the placenta. One differentially methylated CpG was found in the comparison between EOPE and uncomplicated controls. No epigenome-wide significant CpGs were found in the comparisons of LOPE and (un)complicated controls.
[19] Van den Berg 2017 HM 450K DNA methylation significantly differed in EOPE compared with spontaneous preterm birth at 6 CpGs in the placental tissue (hypomethylated), and at 21 CpGs in UC leukocytes (hypermethylated). Moreover, significantly different DNA methylation in EOPE compared with uncomplicated controls was shown at 6 CpGs in the placental tissue and 11 CpGs in uncomplicated controls. No significant associations were shown with LOPE between study groups or tissues. The most differentially methylated CpGs showed hypomethylation in the placental tissue and hypermethylation in UC-WBC.
[52] Zhao 2017 HM 450K There were 2667 DMRs (1433 hypermethylated and 1234 hypomethylated) and 464 DMIs between PE and normotensive controls.
[53] Wilson 2018 HM 450K 1703 sites were differentially methylated in EOPE vs preterm controls, but only a few changes were associated with LOPE compared to term controls in the placenta.
[54] Wang 2019 HM 450K A total of 464 probes reached epigenome-wide significance, whilst 459 (98.9%) were hypomethylated in the EOPE placenta in the Chinese cohort.