273-OR: Association of an Integrated Component of Maternal Glycemic Regulation in Pregnancy with Epigenome-Wide Cord Blood DNA Methylation

Background: Previous studies suggest that fetal programming to hyperglycemia in pregnancy is due to modulation of DNA methylation (DNAm), but they have been limited in their maternal glycemic characterization. Methods: In Gen3G, we used a principal component analysis to integrate multiple glucose and insulin values measured during the second trimester oral glucose tolerance test. We investigated associations between principal components and cord blood DNAm levels in an epigenome-wide analysis among 430 mother–child pairs. Results: The first principal component was robustly associated with lower DNAm at cg26974062 ( TXNIP; p = 9.9 × 10-9) in cord blood. TXNIP is a well-known DNAm marker for type 2 diabetes in adults. Conclusion: We hypothesize that abnormal glucose metabolism in pregnancy may program dysregulation of TXNIP across the life course.

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DNA methylation at LRP1 gene locus mediates the association between maternal total cholesterol changes in pregnancy and cord blood leptin levels

Journal of Developmental Origins of Health and Disease ◽

10.1017/s204017441900076x ◽

2019 ◽

Vol 11 (4) ◽

pp. 369-378 ◽

Cited By ~ 1

Author(s):

Simon-Pierre Guay ◽

Andrée-Anne Houde ◽

Edith Breton ◽

Jean-Patrice Baillargeon ◽

Patrice Perron ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Total Cholesterol ◽

Scavenger Receptor ◽

Ldl Receptor ◽

Density Lipoprotein ◽

First Trimester ◽

Blood Cholesterol ◽

Changes In Pregnancy ◽

In Pregnancy

AbstractPlacental lipids transfer is essential for optimal fetal development, and alterations of these mechanisms could lead to a higher risk of adverse birth outcomes. Low-density lipoprotein receptor (LDLR), LDL receptor-related protein 1 (LRP1), and scavenger receptor class B type 1 (SCARB1) genes are encoding lipoprotein receptors expressed in the placenta where they participate in cholesterol exchange from maternal to fetal circulation. The aim of this study was thus to investigate the association between maternal lipid changes occurring in pregnancy, placental DNA methylation (DNAm) variations at LDLR, LRP1, and SCARB1 gene loci, and newborn’s anthropometric profile at birth. Sixty-nine normoglycemic women were followed from the first trimester of pregnancy until delivery. Placental DNAm was quantified at 43 Cytosine-phosphate-Guanines (CpGs) at LDLR, LRP1, and SCARB1 gene loci using pyrosequencing: 4 CpGs were retained for further analysis. Maternal clinical data were collected at each trimester of pregnancy. Newborns’ data were collected from medical records. Statistical models included minimally newborn sex and gestational and maternal age. Maternal total cholesterol changes during pregnancy (ΔT3-T1) were correlated with DNAm variations at LDLR (r = −0.32, p = 0.01) and LRP1 (r = 0.34, p = 0.007). DNAm at these loci was also correlated with newborns’ cord blood triglyceride and leptin levels. Mediation analysis supports a causal relationship between maternal cholesterol changes, DNAm levels at LRP1 locus, and cord blood leptin concentration (pmediation = 0.02). These results suggest that LRP1 DNAm link maternal blood cholesterol changes in pregnancy and offspring adiposity at birth, which provide support for a better follow-up of blood lipids in pregnancy.

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25-Hydroxyvitamin D in pregnancy and genome wide cord blood DNA methylation in two pregnancy cohorts (MoBa and ALSPAC)

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/j.jsbmb.2016.03.005 ◽

2016 ◽

Vol 159 ◽

pp. 102-109 ◽

Cited By ~ 13

Author(s):

M. Suderman ◽

L.C. Stene ◽

J. Bohlin ◽

C.M. Page ◽

K. Holvik ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Hydroxyvitamin D ◽

Genome Wide ◽

25 Hydroxyvitamin D ◽

In Pregnancy

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Maternal dysglycaemia, changes in the infant’s epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial

PLoS Medicine ◽

10.1371/journal.pmed.1003229 ◽

2020 ◽

Vol 17 (11) ◽

pp. e1003229

Author(s):

Elie Antoun ◽

Negusse T. Kitaba ◽

Philip Titcombe ◽

Kathryn V. Dalrymple ◽

Emma S. Garratt ◽

...

Keyword(s):

Physical Activity ◽

Dna Methylation ◽

Cord Blood ◽

Pregnant Women ◽

Lifestyle Intervention ◽

Standard Care ◽

Physical Activity Intervention ◽

Randomised Control Trial ◽

Oral Glucose ◽

In Pregnancy

Background Higher maternal plasma glucose (PG) concentrations, even below gestational diabetes mellitus (GDM) thresholds, are associated with adverse offspring outcomes, with DNA methylation proposed as a mediating mechanism. Here, we examined the relationships between maternal dysglycaemia at 24 to 28 weeks’ gestation and DNA methylation in neonates and whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia. Methods and findings We investigated 557 women, recruited between 2009 and 2014 from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT), of a lifestyle intervention (low glycaemic index (GI) diet plus physical activity) in pregnant women with obesity (294 contol, 263 intervention). Between 27 and 28 weeks of pregnancy, participants had an oral glucose (75 g) tolerance test (OGTT), and GDM diagnosis was based on diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), with 159 women having a diagnosis of GDM. Cord blood DNA samples from the infants were interrogated for genome-wide DNA methylation levels using the Infinium Human MethylationEPIC BeadChip array. Robust regression was carried out, adjusting for maternal age, smoking, parity, ethnicity, neonate sex, and predicted cell-type composition. Maternal GDM, fasting glucose, 1-h, and 2-h glucose concentrations following an OGTT were associated with 242, 1, 592, and 17 differentially methylated cytosine-phosphate-guanine (dmCpG) sites (false discovery rate (FDR) ≤ 0.05), respectively, in the infant’s cord blood DNA. The most significantly GDM-associated CpG was cg03566881 located within the leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) (FDR = 0.0002). Moreover, we show that the GDM and 1-h glucose-associated methylation signatures in the cord blood of the infant appeared to be attenuated by the dietary and physical activity intervention during pregnancy; in the intervention arm, there were no GDM and two 1-h glucose-associated dmCpGs, whereas in the standard care arm, there were 41 GDM and 160 1-h glucose-associated dmCpGs. A total of 87% of the GDM and 77% of the 1-h glucose-associated dmCpGs had smaller effect sizes in the intervention compared to the standard care arm; the adjusted r2 for the association of LGR6 cg03566881 with GDM was 0.317 (95% confidence interval (CI) 0.012, 0.022) in the standard care and 0.240 (95% CI 0.001, 0.015) in the intervention arm. Limitations included measurement of DNA methylation in cord blood, where the functional significance of such changes are unclear, and because of the strong collinearity between treatment modality and severity of hyperglycaemia, we cannot exclude that treatment-related differences are potential confounders. Conclusions Maternal dysglycaemia was associated with significant changes in the epigenome of the infants. Moreover, we found that the epigenetic impact of a dysglycaemic prenatal maternal environment appeared to be modified by a lifestyle intervention in pregnancy. Further research will be needed to investigate possible medical implications of the findings. Trial registration ISRCTN89971375.

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Birthweight DNA methylation signatures in infant saliva

Clinical Epigenetics ◽

10.1186/s13148-021-01053-1 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Chiara Moccia ◽

Maja Popovic ◽

Elena Isaevska ◽

Valentina Fiano ◽

Morena Trevisan ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Gestational Age ◽

Low Birthweight ◽

Continuous Variable ◽

Linear Regression Models ◽

Association Analyses ◽

Cpg Sites ◽

Adverse Health Outcomes ◽

The Look

Abstract Background Low birthweight has been repeatedly associated with long-term adverse health outcomes and many non-communicable diseases. Our aim was to look-up cord blood birthweight-associated CpG sites identified by the PACE Consortium in infant saliva, and to explore saliva-specific DNA methylation signatures of birthweight. Methods DNA methylation was assessed using Infinium HumanMethylation450K array in 135 saliva samples collected from children of the NINFEA birth cohort at an average age of 10.8 (range 7–17) months. The association analyses between birthweight and DNA methylation variations were carried out using robust linear regression models both in the exploratory EWAS analyses and in the look-up of the PACE findings in infant saliva. Results None of the cord blood birthweight-associated CpGs identified by the PACE Consortium was associated with birthweight when analysed in infant saliva. In saliva EWAS analyses, considering a false discovery rate p-values < 0.05, birthweight as continuous variable was associated with DNA methylation in 44 CpG sites; being born small for gestational age (SGA, lower 10th percentile of birthweight for gestational age according to WHO reference charts) was associated with DNA methylation in 44 CpGs, with only one overlapping CpG between the two analyses. Despite no overlap with PACE results at the CpG level, two of the top saliva birthweight CpGs mapped at genes associated with birthweight with the same direction of the effect also in the PACE Consortium (MACROD1 and RPTOR). Conclusion Our study provides an indication of the birthweight and SGA epigenetic salivary signatures in children around 10 months of age. DNA methylation signatures in cord blood may not be comparable with saliva DNA methylation signatures at about 10 months of age, suggesting that the birthweight epigenetic marks are likely time and tissue specific.

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Associations of circulating folate, vitamin B12 and homocysteine concentrations in early pregnancy and cord blood with epigenetic gestational age: the Generation R Study

Clinical Epigenetics ◽

10.1186/s13148-021-01065-x ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Giulietta S. Monasso ◽

Leanne K. Küpers ◽

Vincent W. V. Jaddoe ◽

Sandra G. Heil ◽

Janine F. Felix

Keyword(s):

Dna Methylation ◽

Vitamin B12 ◽

Cord Blood ◽

Gestational Age ◽

Fetal Development ◽

Maternal Plasma ◽

Plasma Homocysteine ◽

Training Population ◽

Epigenetic Aging ◽

Pregnancy Dating

Abstract Background Circulating folate, vitamin B12 and homocysteine concentrations during fetal development have been associated with health outcomes in childhood. Changes in fetal DNA methylation may be an underlying mechanism. This may be reflected in altered epigenetic aging of the fetus, as compared to chronological aging. The difference between gestational age derived in clinical practice and gestational age predicted from neonatal DNA methylation data is referred to as gestational age acceleration. Differences in circulating folate, vitamin B12 and homocysteine concentrations during fetal development may be associated with gestational age acceleration. Results Up to 1346 newborns participating in the Generation R Study, a population-based prospective cohort study, had both cord blood DNA methylation data available and information on plasma folate, serum total and active B12 and plasma homocysteine concentrations, measured in early pregnancy and/or in cord blood. A subgroup of 380 newborns had mothers with optimal pregnancy dating based on a regular menstrual cycle and a known date of last menstrual period. For comparison, gestational age acceleration was calculated based the method of both Bohlin and Knight. In the total study population, which was more similar to Bohlin’s training population, one standard deviation score (SDS) higher maternal plasma homocysteine concentrations was nominally associated with positive gestational age acceleration [0.07 weeks, 95% confidence interval (CI) 0.02, 0.13] by Bohlin’s method. In the subgroup with pregnancy dating based on last menstrual period, the method that was also used in Knight’s training population, one SDS higher cord serum total and active B12 concentrations were nominally associated with negative gestational age acceleration [(− 0.16 weeks, 95% CI − 0.30, − 0.02) and (− 0.15 weeks, 95% CI − 0.29, − 0.01), respectively] by Knight’s method. Conclusions We found some evidence to support associations of higher maternal plasma homocysteine concentrations with positive gestational age acceleration, suggesting faster epigenetic than clinical gestational aging. Cord serum vitamin B12 concentrations may be associated with negative gestational age acceleration, indicating slower epigenetic than clinical gestational aging. Future studies could examine whether altered fetal epigenetic aging underlies the associations of circulating homocysteine and vitamin B12 blood concentrations during fetal development with long-term health outcomes.

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Resistin in pregnancy: analysis of determinants in pairs of umbilical cord blood and maternal serum

Cytokine X ◽

10.1016/j.cytox.2021.100052 ◽

2021 ◽

pp. 100052

Author(s):

Anne FLOECK ◽

Nina FERRARI ◽

Christine JOISTEN ◽

Maria T. PUTH ◽

Brigitte STRIZEK ◽

...

Keyword(s):

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Maternal Serum ◽

In Pregnancy

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Abstract MP42: Adherence To Healthy Dietary Patterns In Pregnancy And Placental Dna Methylation- An Epigenome Wide Association Study

Circulation ◽

10.1161/circ.143.suppl_1.mp42 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Cuilin Zhang ◽

Jing Wu ◽

Marion Ouidir ◽

Stefanie Hinkle ◽

Fasil Ayele

Keyword(s):

Dna Methylation ◽

Dietary Patterns ◽

First Trimester ◽

Healthy Eating Index ◽

Nervous System Development ◽

Dietary Quality ◽

Analysis Tool ◽

Linear Regression Models ◽

Cpg Sites ◽

In Pregnancy

Background: Accumulating evidence support the intergenerational impacts of diet in pregnancy. The underlying mechanisms, however, remain unclear. Placental epigenetic mechanisms may be involved although data from human epidemiological studies are sparse. We aimed to investigate associations of dietary quality in pregnancy with epigenome-wide placental DNA methylation in a multiracial pregnancy cohort. Methods: DNA methylation was measured using the Illumina Infinium Human Methylation450 Beadchip on placentas obtained at delivery from 301 pregnant women who participated in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort. Dietary information during periconception and early first trimester was collected using food frequency questionnaires, and diet in the second and third trimester was collected using a 24-hour dietary recall during four study visits. Scores for adherence to three healthy dietary patterns, alternate Healthy Eating Index (aHEI), alternate Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH), were calculated. For associations of each dietary pattern score with methylation, we conducted analyses using robust linear regression models after the adjustment for age, pre-pregnancy body mass index, race/ethnicity, physical activity, total energy intakes, and population stratification. Genes annotating the top significant CpG sites (false discovery rate (FDR) adjusted P<0.05) were queried for enrichment of functional pathways using the Ingenuity Pathway Analysis tool. Results: Adherence to aHEI was significantly associated with methylation of 8 CpG sites, with the most significant association manifested in cg16724319- MDH1B (P=1.9x10 -10 ). Adherence to aMED was related to methylation of 14 CpG sites, with the most significant association manifested in cg07835181- CLCN7 (P=1.7x10 -11 ). DASH was significantly related to 33 CpG sites, with the most significant association manifested in cg26292547- REV3L (P=4.4x10 -10 ). Further, genes annotating the significant CpG sites were enriched in pathways related to cardiovascular and nervous system development and function, cancer, organismal injury and abnormalities, and reproductive system diseases. Conclusion: Findings from the epigenome wide study suggest that overall dietary quality in pregnancy is associated with placental DNA methylation changes at different loci potentially related to cardiovascular, neurological, reproductive, and cancer phenotypes.

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