Placental DNA methylation in pregnancies complicated by maternal diabetes and/or obesity: State of the art and research gaps

Figures & data

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/m^2 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.

Table 2. Literature search on studies of DNA methylation in placenta tissue and hyperglycaemia and dyslipidemia in pregnancy.

Sample size	Method	Genes	Results	Influence of foetal sex	Authors, year, PMID
Dyslipidemia
Placenta, 3rd trimester
262	450k EWAS	STK11, MOGAT2, DHRS12, BRD1, ECI2, SRM, ALX4, MICA, RPTOR, FAAH, HECTD2	11 CpGs in 11 genes associated with maternal dyslipidemia (after FDR).	Adjusted for foetal sex	Ouidir et al, 2020 [119]
69	PS	LDLR, LRP1, SCARB1	Maternal cholesterol changes were negatively associated with LDLR DNAm and positively associated with LRP1 DNAm. LDLR and LRP1 DNAm was associated with cord blood triglyceride and leptin levels. Mediation analysis supported a causal relationship between cholesterol changes, LRP1 DNAm, and cord blood leptin level.	Adjusted for foetal sex	Guay et al, 2019 [120]
262	450k EWAS	The Horvath Clock	Low maternal HDL cholesterol associated with accelerated placental epigenetic ageing among mothers with normal pre-pregnancy weight and a female foetus.	Adjusted and stratified for foetal sex	Shrestha et al, 2019 [55]
Hyperglycaemia
Placenta, 3rd trimester
259	EPIC EWAS	LEP	Maternal glycaemia associated with LEP DNAm, neonatal leptinemia, and adiposity and skinfolds at age 3 years. DNAm levels at cg15758240 mediates 0.8% of the association between maternal glycaemia and neonatal leptinemia.	Adjusted for foetal sex X/Y probes removed	Gagné-Ouellet et al, 2020 [50]
430	EPIC EWAS	CHRNA4, MICALL2/ UNCX, DLGAP2, ENTPD2, DP1P	DNAm at 188 CpG sites was associated with Matsuda index (after FDR). Mendelian randomization analyses found five loci where DNAm may causally influence maternal insulin sensitivity, including the maternally imprinted gene DLGAP2.	Adjusted for foetal sex X/Y probes removed	Hivert et al, 2020 [65]
12 decreased GI 12 increased GI	PS, 450k EWAS	PLIN1, CPT1B, SSTR4, CIDEA	Negative association between DNAm and miRNA expression*.	No data on foetal sex X/Y probes removed	Yan et al, 2019 [121]
448	EPIC EWAS	PDE4B, TNFRSF1B, LDLR, BLM	DNAm of PDE4B, NFRSF1B, LDLR, and BLM associated (after FDR) with 2 hr glucose post OGTT. DNAm and mRNA expression of PDE4B, TNFRSF1B and LDLR was negatively correlated. In an independent replication the results were consistent in direction.	Adjusted for foetal sexX/Y probes removed	Cardenas et al, 2018 [122]
24 GDM 34 Ctrl	PS	PGC1A	In combined groups, DNAm associated positively with fasting, 1 hr, and 2 hr glucose levels post OGTT.	Adjusted for foetal sex	Xie et al, 2015 [47]
34 IGT 106 NGT	PS	IGF1R, IGFBP3, IGF1, INSR	DNAm of IGF1R and IGFBP3 were lower in IGT compared to NGT and associated negatively with fasting (IGF1R) and 2 hr glucose levels (IGF1R and IGFBP3) post OGTT.	Adjusted for foetal sex	Desgagné et al, 2014 [123]
26 IGT 74 NGT	PS	ABCA1	DNAm at maternal side was positively associated with 2 hr glucose levels post OGTT.	Adjusted for foetal sex (partly)	Houde et al, 2013 [124]
98	PS	ADIPOQ	Foetal side DNAm associated negatively with 2hr glucose post OGTT. Maternal side DNAm associated negatively with HOMA-IR. DNAm at both sides associated negatively with maternal adiponectin levels	No data on foetal sex	Bouchard et al, 2012 [53]

If FDR is not stated in the table, it was not stated in the paper.

*Yan et al did not include continuous data on glycaemic index (GI).

Abbreviations: DNAm: DNA methylation, GI: glycaemic index, OGTT: oral glucose tolerance test, IGT: impaired glucose tolerance, NGT: Normal glucose tolerance, FDR: false discovery rate, EWAS: epigenome wide association study, PS: pyrosequencing.

Table 3. Differentially methylated genes identified in literature search.

Genes	Exposure	Authors	Imprinted gene		Genes	Exposure	Authors	Imprinted gene
ABCA1	Hyperglycaemia	Houde et al [124]			LDLR	Dyslipidemia	Guay et al [120]
AC092377.1	Pre-pregnancy BMI	Shrestha et al [115]			LDLR	Hyperglycaemia	Cardenas et al [122]
ADIPOQ	Hyperglycaemia	Bouchard et al [53]			LEP	GDM	el Hajj et al [66]
ADIPOQ	Obesity	Haghiac et al [51]			LEP	GDM and Obesity	Lesseur et al [48]
ADIPOQ	Obesity	Nogues et al [52]			LEP	Hyperglycaemia	Gagné-Ouellet et al [50]
ADIPOR1	Obesity	Nogues et al [52]			LEP	Obesity	Haghiac et al [51]
ALU repeat	GDM	el Hajj et al [66]			LEP	Obesity	Nogues et al [52]
ALX4	Dyslipidemia	Ouidir et al [119]			LEP	GDM	Sletner et al [90]
APC	GDM	el Hajj et al [66]			LEPR	Obesity	Nogues et al [52]
ARMCX6	GDM	Petropoulos et al [104]			LINE1 repeat	GDM	el Hajj et al [66]
BDP1P	Hyperglycaemia	Hivert et al [65]			LIT1	GDM	el Hajj et al [66]		X
BLM	Hyperglycaemia	Cardenas et al [122]			LPL	GDM	Gagné-Ouellet et al [50]
BMP7	GDM	Cote et al [45]			LPL	GDM	Houde et al [105]
BRCA1	Obesity	Hoch et al [112]			LRP1	Dyslipidemia	Guay et al [120]
BRD1	Dyslipidemia	Ouidir et al [119]			LRP1B	GDM	Houde et al [69]
BRD2	GDM	Houde et al [69]			MEG3	GDM	el Hajj et al [66]		X
C19MC	Pre-pregnancy BMI	Prats-Puig et al [116]			MEG3	GDM	Chen et al [92]		X
CCDC181	GDM	Binder et al [102]			MEST	GDM	el Hajj et al [66]		X
CCDC97	Obesity	Ghildayal et al [114]			MICA	Dyslipidemia	Ouidir et al [119]
CHRNA4	Hyperglycaemia	Hivert et al [65]			MICALL2/UNCX	Hyperglycaemia	Hivert et al [65]
CIDEA	Hyperglycaemia	Yan et al [121]			MOGAT2	Dyslipidemia	Ouidir et al [119]
CPT1B	Hyperglycaemia	Yan et al [121]			NDUFB6	GDM	el Hajj et al [66]
CRHBP	Obesity	Ghildayal et al [114]			NESPAS	GDM	el Hajj et al [66]		X
CTBP2	GDM	Cote et al [45]			NOTCH1	GDM and T2DM	Shimanuki et al [111]
CYBA	GDM and T2DM	Alexander et al [39]			NR3C1	GDM	el Hajj et al [66]
CYP24A1	GDM	Wang et al [44]			NXN	GDM and T2DM	Alexander et al [39]
CYP27B1	GDM	Wang et al [44]			OAS1	GDM	Zhang et al [97]
DCAF11	GDM	Petropoulos et al [104]			OCT4	GDM	el Hajj et al [66]
DGKZ	GDM	Petropoulos et al [104]			PDE4B	Hyperglycaemia	Cardenas et al [122]
DHRS12	Dyslipidemia	Ouidir et al [119]			PDX1	GDM	Wang et al [44]
DLGAP2	GDM	Houde et al [69]		X	PEG3	GDM	el Hajj et al [66]		X
DLGAP2	Hyperglycaemia	Hivert et al [65]		X	PGC1a	GDM	Wang et al [44]
DLK1	GDM	Zhao et al [95]		X	PGC1a	GDM	Cote et al [45]
DLL1	GDM and T2DM	Shimanuki et al [111]			PGC1a	GDM	Liu et al [40]
ECI2	Dyslipidemia	Ouidir et al [119]			PGC1a	GDM and T2DM	Jiang et al [46]
EGFL7	Pre-pregnancy BMI	Shrestha et al [115]			PGC1a	Hyperglycaemia	Xie et al [47]
ENTPD2	Hyperglycaemia	Hivert et al [65]			PIWIL3	GDM and T2DM	Alexander et al [39]
ESR1	GDM	Knabl et al [108]			PLIN1	Hyperglycaemia	Yan et al [121]
FTO	GDM	Franzago et al [91]			POLR2G	GDM	Zhang et al [97]
FAAH	Dyslipidemia	Ouidir et al [119]			PPARA	GDM	Rong et al [101]
G6PD	GDM	Steyn et al [96]			PPARA	GDM	el Hajj et al [66]
GLUT3	GDM	Rong et al [101]			PPIA	GDM	Zhang et al [97]
GLUT3	GDM	Liu et al [40]			PRDM16	GDM	Cote et al [45]
GSTM1	GDM and T2DM	Alexander et al [39]			RBP4	GDM	Rong et al [101]
GSTM5	GDM and T2DM	Alexander et al [39]			RBP4	GDM	Liu et al [40]
H19	GDM	el Hajj et al [66]		X	RETN	GDM	Rong et al [101]
HECTD2	Dyslipidemia	Ouidir et al [119]			RPTOR	Dyslipidemia	Ouidir et al [119]
HLA-DOA	GDM	Binder et al [102]			SCARB1	Dyslipidemia	Guay et al [120]
HLA-H/J	GDM	Binder et al [102]			SLC6A4	GDM	Blazevic et al [99]
HTR2A	GDM	Horvatiček et al [89]			SNRPN	GDM	el Hajj et al [66]		X
ICAM-1	GDM	Diaz-Perez et al [110]			SNRPN	GDM	Binder et al [102]		X
IGF1	Hyperglycaemia	Desgagné et al [123]			SRM	Dyslipidemia	Ouidir et al [119]
IGF1R	Hyperglycaemia	Desgagné et al [123]		X	SRM	Dyslipidemia	Ouidir et al [119]
IGFBP1	GDM	Steyn et al [96]			SSTR4	Hyperglycaemia	Yan et al [121]
IGFBP2	GDM	Steyn et al [96]			STK11	Dyslipidemia	Ouidir et al [119]
IGFBP3	Hyperglycaemia	Desgagné et al [123]			TBR1	GDM	Petropoulos et al [104]
IGFBP6	GDM	Steyn et al [96]			TKT	GDM	Steyn et al [96]
IL10	GDM	el Hajj et al [66]			TNFRSF1B	Hyperglycaemia	Cardenas et al [122]
INSR	Hyperglycaemia	Desgagné et al [123]			VEZT	Pre-pregnancy BMI	Shrestha et al [115]
KCNE1	GDM and T2DM	Alexander et al [39]

Abbreviations: GDM: Gestational Diabetes Mellitus, T2DM: Type 2 Diabetes Mellitus, BMI: body mass index.

Figure 1. Overview of literature search strategy and screening of included and excluded original research papers.

Figure 2. Percental overviews of number of studies conducted stratifying: A. by disease or trait, B. by placental tissue type, and C. by methodology. Abbreviations: GDM: Gestational Diabetes Mellitus, T1DM: Type 1 Diabetes Mellitus, T2DM: Type 2 Diabetes Mellitus, 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.

Table 4. Differentially methylated imprinted genes.

Genes	Protein/transcript	Chr. locus	Parental origin	Exposure	Change with exposure	Authors	Function (related to development of placenta and foetus)
C19MC	Chromosome 19 microRNA cluster	19q13.41	P	Pre-pregnancy BMI	↓	Prats-Puig et al [116]	miRNA cluster consisting of 46 genes, encoding 59 mature miRNAs, that are primate-specific and exclusively expressed in the placenta, embryonic stem cells and few cancers [63].
DLGAP2	DLG Associated Protein 2	8p23.3	M	GDM	↑	Houde et al [69]	Methylation may causally influence maternal insulin sensitivity [65].
DLGAP2				Hyperglycaemia	↑	Hivert et al [65]
DLK1	Delta Like Non-Canonical Notch Ligand 1	14q32.2	P	GDM	↑	Zhao et al [95]	DLK1-MEG3 imprinting locus associated with T1DM risk [125]. Predominant placental expression in vascular endothelial cells and pericytes, may play a pivotal role in development of these cells in placenta [126]. Hypomethylated DLK1 and H19 detected in Beckwith-Wiedeman-Syndrome [127]. Placental expression at term, but not in first trimester, tended to correlate with birthweight [57].
H19	long non-coding RNA	11p15	M	GDM	ns.	el Hajj et al [66]	Placental expression in first trimester, but not at term, correlated with crown rump length and tended to correlate with birth weight [57].
LIT1/ KCNQ1OT1	non-coding RNA	11p15.5	P	GDM	ns.	el Hajj et al [66]	Major genetic locus of Beckwith-Wiedeman-Syndrome [128]. Placental expression also altered in intrauterine growth restriction [128].
MEG3	Maternally Expressed 3	14q32.3	M	GDM	ns.	el Hajj et al [66]	Reduced expression in Intrauterine growth restriction [129]. Expression not correlated with birth weight or placental weight [57]. DLK1-MEG3 imprinting locus associated with T1DM risk [125].
MEG3				GDM	↑	Chen et al [92]
MEST	Mesoderm Specific Transcript	7q32.2	P/biallelic	GDM	↓	el Hajj et al [66]	Monoallelic expression in 81% of term placenta samples [57]. Differentially methylated in placentas of Small and large for gestational age [130]. No correlation between methylation and expression [130]. No expression correlation with birth weight [57]. Reduced placental methylation and increased expression in second trimester idiopathic spontaneous abortion [131].
NESPAS	long non-coding RNA	20q13.32	P	GDM	↓	el Hajj et al [66]	Antisense to NESP; encodes neuroendocrine secretory protein 55 in endocrine and brain tissues, considered neuron-specific [132]. Nothing known in placenta.
PEG3	Paternally Expressed 3	19q13.4	P/biallelic	GDM	ns.	el Hajj et al [66]	Monoallelic expression in 88% of term placenta samples [57]. Cord blood PEG3 methylation associates with placental weight [133]. Reduced expression in Intrauterine growth restriction [129]. No correlation between expression and birth weight [57].
SNRPN	SmallNuclear RibonucleoproteinPolypeptide N	15q11.2	P	GDM	ns.	el Hajj et al [66]	DNAm variation regulate normal placentation and placental disorders, is potentially susceptible to folic acid supplementation, and may be useful as novel foetal DNA marker in maternal plasma [134].
SNRPN				GDM	ns.	Binder et al [102]

Abbreviations: ns: non-significant, GDM: Gestational Diabetes Mellitus, T1DM: Type 1 Diabetes Mellitus, DNAm: DNA methylation.

Lu S, Wang J, Kakongoma N, et al. DNA methylation and expression profiles of placenta and umbilical cord blood reveal the characteristics of gestational diabetes mellitus patients and offspring. Clin Epigenetics. [Internet]. 2022;14(1):69. Available from: http://www.ncbi.nlm.nih.gov/pubmed/35606885

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Data Availability Statement

Data is contained within the article and can be accessed from the corresponding authors on reasonable request.