Table 1.
Literature search on studies of DNA methylation in placenta tissue and diabetes and obesity in pregnancy.
| Sample size | Method | Genes | Results | Influence of foetal sex | Authors, year | |
|---|---|---|---|---|---|---|
| GDM | ||||||
| Placenta, 3rd trimester | ||||||
| 21 GDM 20 Ctrl |
RRBS | 2,799 CpG sites with changes of DNAm after adjustment for maternal BMI. Pathway analysis found DNAm changes related to T2D and insulin resistance pathways. | No data on foetal sex | Lu et al, 2022 [88] | ||
| 80 GDM 119 Ctrl |
PS | HTR2A | Increased pre-pregnancy BMI and GDM was independently associated with lower promoter DNAm in female but not male placentas. | Stratified for foetal sex | Horvatiček et al, 2022 [89] | |
| 34 GDM 46 Ctrl |
PS | LEP | Higher DNAm in placenta from women with GDM of South Asian ethnicity but not European ethnicity. | No data on foetal sex | Sletner et al, 2021 [90] | |
| 33 GDM 27 Ctrl |
PS | FTO | No association between FTO DNAm and GDM. | No data on foetal sex | Franzago et al, 2021 [91] | |
| 23 GDM 23 Ctrl |
MethylTarget Technique |
MEG3 | DNAm was increased in GDM, and positively associated with birthweight and fasting glucose levels. | No data on foetal sex | Chen et al, 2021 [92] | |
| 20 GDM 16 Ctrl |
450k EWAS | 662 CpGs with differential DNAm in GDM (without FDR). Pathway analysis found DNAm changes related to polyamines, amines, and vitamin B6 metabolism pathways. | Adjusted for foetal sexX/Y probes removed | Awamleh et al, 2021 [93] | ||
| 41 GDM 40 Ctrl |
MS-PCR | CYP24A1, CYP27B1 | No difference in DNAm between GDM and Ctrl. | No data on foetal sex | Wang et al, 2020 [94] | |
| 15 GDM 15 Ctrl |
MethylTarget Technique |
DLK1 | Higher DNAm at both foetal and maternal side. DNAm associated with birthweight and 2 hr glucose levels post OGTT. | No data on foetal sex | Zhao et al, 2019 [95] | |
| 6 GDM 6 Ctrl |
MS-PCR | G6PD, IGFBP, TKT, IGFBP2, IGFBP6 | Higher DNAm of IGFBP1, IGFBP2 and IGFBP6, which also were pos. associated with maternal glucose levels at fasting and 1 hr, but not at 2 hrs, post OGTT. | Only females | Steyn et al, 2019 [96] | |
| 32 GDM 31 Ctrl |
450k EWAS | OAS1, PPIA, POLR2G | 24,577 CpG sites with changes of DNAm (without FDR). Pathway analysis identified OAS1, PPIA and POLR2G as possible pathogenic genes of GDM, based on protein-protein interaction analysis. | No data on foetal sex | Zhang et al, 2018 [97] | |
| 20 GDM 20 Ctrl |
BS | PGC1A, PDX1 | Higher PGC1A DNAm in GDM. | No data on foetal sex | Wang et al, 2018 [44] | |
| 24 GDM 42 Ctrl |
PS | LPL | Out of 20 CpGs, one had lower DNAm in GDM, and one was positively associated with birth- and childhood weight Z-scores and fat mass, and negatively with lean mass. | Adjusted for foetal sex | Gagne-Ouellet et al, 2017 [98] |
|
| 18 GDM 32 Ctrl |
BS | SLC6A4 | Average DNAm was 27% lower in GDM and negatively associated with expression and fasting glucose levels. All were caesarean sections, and biopsies were from foetal side. | No association with foetal sex | Blazevic et al, 2017 [99] | |
| 56 GDM 974 Ctrl |
LC-MS/MS | Higher DNAm in GDM across the epigenome. The quintile with highest degree of DNAm has the strongest representation of GDM, whereas Q1-4 had equal GDM numbers. | Adjusted for foetal sex | Reichetzeder et al, 2016 [100] |
||
| 133 GDM 100 Ctrl |
PS, 450k EWAS |
PGC1A, PRDM16, BMP7, CTBP2 | GDM was associated with DNAm of PGC1A, PRDM16 and BMP7. DNAm of PGC1A and PRDM16 was associated with cord blood leptin. DNAm of PGC1A explained 0.8% of variation of cord leptin levels, independent of maternal fasting glucose. | Adjusted for foetal sex | Coté et al, 2016 [45] | |
| 36 GDM 40 Ctrl |
PS, MEDIP |
RBP4, GLUT3, RETN, PPARA | DNAm of 4699 DMRs were altered in GDM. Pathway analysis identified cell death and cell regulation, immune/inflammatory response, and nervous system development as top pathways. RBP4, GLUT3, RETN and PPARA were validated by PS. | No data on foetal sex | Rong et al, 2015 [101] | |
| 20 GDM 60 Ctrl |
PS | DLGAP2, LRP1B, BRD2 | No difference in average DNAm between GDM and Ctrl, but one CpG of DLGAP2 had higher DNAm in GDM. LRP1B and BRD2 DNAm associated with glucose levels in Ctrls. | Adjusted for foetal sex | Houde et al, 2015 [69] | |
| 41 GDM 41 Ctrl |
PS, 450k EWAS | CCDC181, HLA-H/J, HLA-DOA, SNRPN | DNAm did not differ between GDM and Ctrl (after FDR). Four selected CpGs of top 20 could not be validated in a separate cohort. | Adjusted for foetal sex X/Y probes removed |
Binder et al, 2015 [102] | |
| 25 GDM 18 Ctrl |
450k EWAS | 1708 CpGs had more than 5% higher or lower DNAm in GDM (after FDR). Pathway analysis identified endocytosis, MAPK signalling and metabolic processes. | No data on foetal sex X/Y probes removed |
Finer et al, 2015 [103] | ||
| 7 GDM 7 Ctrl |
PS, 450k EWAS |
DGKZ, ARMCX6, TBR1, DCAF11 | 2021 CpGs (981 genes) showed differential DNAm in GDM. DGKZ, ARMCX6, DCAF11 and TBR1 were validated by PS. | Only males | Petropoulos et al, 2015 [104] |
|
| 28 GDM 30 Ctrl |
BS, 385k Island EWAS | GLUT3, RBP4, PGC1A | GLUT3 DNAm was higher and RBP4 and PGC1A DNAm was lower in GDM. 5% of the DMRs (total 10,424) were located on autosomes. | No data on foetal sex X/Y probes included |
Liu et al, 2014 [40] | |
| 27 GDM 99 Ctrl |
PS | LPL | DNAm was lower in GDM. Two CpGs were negatively associated with 2 hr glucose levels, post OGTT. DNAm at one intron CpG explained up to 26% of LPL mRNA. | Adjusted for foetal sex | Houde et al, 2014 [105] | |
| 30 GDM 14 Ctrl |
450k EWAS | DNAm of 8657 CpGs (3271 genes) were changed in GDM (without FDR). Pathway analysis identified cardiovascular disease as top hit. | Adjusted for foetal sex X/Y probes removed |
Ruchat et al, 2013 [106] | ||
| 16–29 diet-treated GDM 18–34 insulin-treated GDM 21–50 Ctrl |
PS | H19, MEG3, IT1, MEST, NESPAS, LEP, PEG3, APC, SNRPN, NR3C1, PPARA, DUFB6, OCT4, IL10, ALU, LINE1 | Lower DNAm of MEST, NESPAS, NR3C1, PPAPA, ALU and LINE1 in GDM compared to controls. However, the control group were all non-smokers, whereas the GDM group had smokers, which may confound the results, since smoking affects foetal DNAm [107]. | No association with foetal sex | El Hajj et al, 2013 [49] | |
| Placenta and Decidua, 3rd trimester | ||||||
| 40 GDM 40 Ctrl |
MS-PCR | ESR1 | DNAm of ESR1 was not detected in placenta of GDM and Ctrls, but in decidua of Ctrls. | Adjusted for foetal sex | Knabl et al, 2015 [108] | |
| FPECs, 3rd trimester | ||||||
| 9 GDM 9 Ctrl |
450k EWAS | 2617 CpGs (2063 genes) in dAEC and 1568 CpGs (1360 genes) in dVEC showed DNAm changes in GDM (without FDR). Six genes altered by GDM in both dAEC and dVEC were associated with actin reorganization processes. | Adjusted for foetal sex X/Y probes removed |
Cvitic et al, 2018 [109] | ||
| 5 GDM 9 Ctrl |
450k EWAS | ICAM1 | No difference in DNAm between GDM and Ctrl. | Adjusted for foetal sex X/Y probes removed |
Diaz-Perez et al, 2016 [110] |
|
| GDM and T2DM | ||||||
| Placenta, 3rd trimester | ||||||
| 16 GDM 7 T2DM 23 Ctrl |
EPI-JET | PGC1A | In GDM and T2DM, DNAm at one CpG was higher in male offspring placentas. | Stratified for foetal sex | Jiang et al, 2020 [46] | |
| 14 GDM 3 T2DM 17 Ctrl |
450k EWAS | PIWIL3, CYBA, STM1, GSTM5, KCNE1, NXN | DNAm was changed in GDM at 465 CpGs of male offspring, at 247 CpGs of female offspring, and at 277 CpGs when sexes were combined (without FDR). DNAm changes were found at loci related to mitochondrial function, DNA repair, inflammation, oxidative stress. DNAm was negatively associated with mRNA and protein levels for PIWIL3, CYBA, GSTM1, GSTM5, KCNE1 and NXN. | Stratified for foetal sex | Alexander et al, 2018 [39] | |
| 2 GDM 3 T2DM 12 Ctrl |
MS-PCR | DLL1, NOTCH1 | No difference in DNAm between GDM, T2DM and Ctrls, but DNAm associated with other pregnancy complications. | No data on foetal sex | Shimanuki et al, 2015 [111] | |
| Obesity and pre-pregnancy BMI | ||||||
| Placenta, 1st trimester | ||||||
| 15 Obese 15 Lean |
EPIC EWAS | BRCA1 | No difference in DNAm between obese and Ctrls. | Adjusted for foetal sex X/Y probes removed |
Hoch et al, 2020 [112] | |
| Placenta, 3rd trimester | ||||||
| 11 Obese 12 Ctrl |
MethylFlash ELISA | Global DNAm was incr. in obese pregnancies. | No data on foetal sex | Shen et al, 2022 [113] | ||
| 437 | EPIC EWAS | CRHBP, CCDC97 | Higher early pregnancy BMI associated with higher DNAm in CRHBP and with lower DNAm of CCDC97, in paired analysis of placenta and cord blood. | Adjusted for foetal sex X/Y probes removed |
Ghildayal et al, 2021 [114] | |
| 301 | 450k EWAS | The Horvath Clock | Negative association between placental epigenetic age acceleration and maternal pre-pregnancy BMI in male offspring only. | Adjusted and stratified for foetal sex | Workalemahu et al, 2021 [56] | |
| 301 | 450k EWAS | EGFL7, VEZT, AC092377.1 | Each 1 kg/m2 increase in maternal pre-pregnancy BMI was associated with 0.09% higher EGFL7 DNAm, 0.13% higher VEZT DNAm, and 0.07% lower AC092377.1 DNAm (after FDR). EGFL7 DNAm associated negatively with mRNA expression. The 3-phosphoinositide degradation pathway was enriched with pre-pregnancy BMI-associated DNAm. | Adjusted for foetal sex | Shrestha et al, 2020 [115] | |
| 72 Mothers 63 Fathers |
PS | C19MC | Lower DNAm associated with maternal BMI and with offspring size at 6 yrs. | Adjusted for foetal sex | Prats-Puig et al, 2020 [116] | |
| 12 Obese 18 Ctrl |
PS | LEP, LEPR, ADIPOQ, ADIPOR1 | Higher LEP DNAm at foetal side only. Lower ADIPOQ DNAm and higher ADIPOR1 DNAm at maternal side only. | No data on foetal sex | Nogues et al, 2019 [52] | |
| 10 Obese 10 Ctrl |
MEDIP | DNAm. 21% higher and hydroxyDNAm 31% lower, in obese compared to Ctrls. Enrichment in DNAm and hydroxyDNAm at chromosomes 17 and 19. | No data on foetal sex | Mitsuya et al, 2017 [117] | ||
| 20 Obese 20 Ctrl |
PS | LEP, ADIPOQ | No difference in LEP DNAm in obese compared to Ctrls. ADIPOQ DNAm was not detected in any of the groups. | No data on foetal sex | Haghiac et al, 2014 [51] | |
| GDM and Obesity | ||||||
| Placenta, 3rd trimester | ||||||
| 7–8 GDM 17–18 Obese |
LUMA | Global DNAm was associated with GDM and obesity in opposite directions. Global DNAm was negatively associated with newborn body length and head circumference. | Non-adjusted and adjusted for foetal sex | Nomura et al, 2014 [118] | ||
| 47 GDM 135 Obese 353 Ctrl |
PS | LEP | DNAm was higher in GDM and in GDM and obesity combined. Obesity alone did not have effect. DNAm was higher in male offspring placentas (all groups together). | Adjusted for foetal sex | Lesseur et al, 2014 [48] | |
If FDR is not stated in the table, it was not stated in the original paper.
Abbreviations: GDM: Gestational Diabetes Mellitus, Ctrl: Control, DNAm: DNA methylation, BMI: body mass index, DMR: differentially methylated region, OGTT: oral glucose tolerance test, FDR: false discovery rate, RRBS: reduced representation bisulphite sequencing, LC-MS/MS: liquid chromatography with tandem mass spectrometry, LUMA: Luminometric Methylation Assay, EWAS: epigenome wide association study, MEDIP: methylated DNA immunoprecipitation, BS, bisulphite sequencing, MS-PCR: methylation-specific PCR, PS: pyrosequencing.