Epigenome-Wide Association Study of Maternal Hemoglobin A1c in Pregnancy and Cord Blood DNA Methylation

Juvinao-Quintero, Diana L.; Starling, Anne P.; Powe, Camille E.; Perron, Patrice; Bouchard, Luigi; Dabelea, Dana; Hivert, Marie‐France

doi:10.2217/epi-2020-0279

Cited by 6 publications

(9 citation statements)

References 69 publications

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“…Cord blood DNAm at cg26974062 had a nominal association with maternal 1-h glucose in the UK Pregnancies Better Eating and Activity Trial (UPBEAT) ( 5 ). Next, we checked recently published data on maternal HbA 1c levels and cord blood DNAm (Gen3G [ N = 412]) ( 8 ), and both TXNIP probes showed nominal associations with maternal HbA 1c (cg02988288, β [SE] −4.5 [0.16], P nominal = 3.9 × 10 −3 ; cg26974062, −3.8 [1.5], P nominal = 0.012) in a direction consistent with that of our AUC gluc and FG meta-analyses. None of the other CpGs with suggestive associations in Table 2 were associated with maternal HbA 1c .…”

Section: Resultsmentioning

confidence: 99%

“…In "reverse lookups," we found little evidence for the reported associations with maternal FG and 1-h or 2-h glucose from UPBEAT participants cord blood analyses: only 5 of 609 reported CpGs for 1-h or 2-h glucose were nominally associated with AUC gluc with the same direction of effect (namely, cg24914185, cg13874780, cg04322572, cg03795071, and cg23913963) (5). Cord blood DNAm at a CpG near URGCP reportedly associated with maternal HbA 1c (8) was not associated with any glycemic trait in our meta-analyses (P nominal > 0.074), and none of the CpGs located in DMRs identified for GDM in a prior PACE report were associated either (9) (P nominal > 0.18).…”

Section: Lookups In Literaturementioning

confidence: 86%

“…We are unable to test the influence of gestational timing of maternal glycemic exposures. However, in a recent study with comparison of the association between early and late measures of maternal HbA 1c during pregnancy and cord blood DNAm, no evidence was found for robust associations related to early pregnancy exposure ( 8 ).…”

Section: Discussionmentioning

confidence: 99%

“…The latter relationships are hypothesized to be mediated by alterations in epigenetic factors, including DNA methylation (DNAm), laid down during prenatal development (4). Single cohort studies have reported associations between GDM or maternal glycemic measures and offspring DNAm (5)(6)(7)(8). The most comprehensive study to date has been a Pregnancy and Childhood Epigenetics (PACE) consortium metaanalysis of epigenome-wide association studies (EWAS) with assessment of the association between GDM diagnosis and cord blood DNAm (9).…”

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confidence: 99%

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Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies

et al. 2022

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OBJECTIVE Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring, a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations. RESEARCH DESIGN AND METHODS To address this hypothesis, we conducted fixed-effects meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmaximum = 3,503), insulin (Nmaximum = 2,062), and area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (Nmaximum = 1,505). We performed lookup analyses for identified cytosine-guanine dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression. RESULTS Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β [SE] = 0.013 [2.1 × 10−3], P value corrected for false discovery rate [PFDR] = 5.1 × 10−3) and cg02988288 (β [SE]−0.013 [2.3 × 10−3], PFDR = 0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm. CONCLUSIONS Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent lookup analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses.

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Section: Resultsmentioning

confidence: 99%

Section: Lookups In Literaturementioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies

et al. 2022

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“…CYP2E1 (cytochrome P450 2E1) is an abundant hepatic enzyme which participates in arachidonic acid metabolism. SNPs in the gene coding for CYP2E1, including C-1054T, are thought to affect lipid metabolism and insulin resistance, and have been was associated with GDM risk ( 27 , 99 ). Concurrently, metabolites of arachidonic acid produced by CYP450 enzymes, known as epoxyeicosatrienoic acids (EETs), are proposed to enhance insulin sensitivity and glucose metabolism.…”

Section: Subsectionsmentioning

confidence: 99%

Multigenerational diabetes mellitus

Thornton,

Shah,

Lillycrop

et al. 2024

Front. Endocrinol.

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Gestational diabetes (GDM) changes the maternal metabolic and uterine environment, thus increasing the risk of short- and long-term adverse outcomes for both mother and child. Children of mothers who have GDM during their pregnancy are more likely to develop Type 2 Diabetes (T2D), early-onset cardiovascular disease and GDM when they themselves become pregnant, perpetuating a multigenerational increased risk of metabolic disease. The negative effect of GDM is exacerbated by maternal obesity, which induces a greater derangement of fetal adipogenesis and growth. Multiple factors, including genetic, epigenetic and metabolic, which interact with lifestyle factors and the environment, are likely to contribute to the development of GDM. Genetic factors are particularly important, with 30% of women with GDM having at least one parent with T2D. Fetal epigenetic modifications occur in response to maternal GDM, and may mediate both multi- and transgenerational risk. Changes to the maternal metabolome in GDM are primarily related to fatty acid oxidation, inflammation and insulin resistance. These might be effective early biomarkers allowing the identification of women at risk of GDM prior to the development of hyperglycaemia. The impact of the intra-uterine environment on the developing fetus, “developmental programming”, has a multisystem effect, but its influence on adipogenesis is particularly important as it will determine baseline insulin sensitivity, and the response to future metabolic challenges. Identifying the critical window of metabolic development and developing effective interventions are key to our ability to improve population metabolic health.

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Maternal glycemia in pregnancy is longitudinally associated with blood DNAm variation at the FSD1L gene from birth to 5 years of age

et al. 2023

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Background In utero exposure to maternal hyperglycemia has been associated with an increased risk for the development of chronic diseases in later life. These predispositions may be programmed by fetal DNA methylation (DNAm) changes that persist postnatally. However, although some studies have associated fetal exposure to gestational hyperglycemia with DNAm variations at birth, and metabolic phenotypes in childhood, no study has yet examined how maternal hyperglycemia during pregnancy may be associated with offspring DNAm from birth to five years of age. Hypothesis Maternal hyperglycemia is associated with variation in offspring DNAm from birth to 5 years of age. Methods We estimated maternal hyperglycemia using the area under the curve for glucose (AUCglu) following an oral glucose tolerance test conducted at 24–30 weeks of pregnancy. We quantified DNAm levels in cord blood (n = 440) and peripheral blood at five years of age (n = 293) using the Infinium MethylationEPIC BeadChip (Illumina). Our total sample included 539 unique dyads (mother–child) with 194 dyads having DNAm at both time-points. We first regressed DNAm M-values against the cell types and child age for each time-point separately to account for the difference by time of measurement for these variables. We then used a random intercept model from the linear mixed model (LMM) framework to assess the longitudinal association between maternal AUCglu and the repeated measures of residuals of DNAm. We adjusted for the following covariates as fixed effects in the random intercept model: maternal age, gravidity, smoking status, child sex, maternal body mass index (BMI) (measured at first trimester of pregnancy), and a binary variable for time-point. Results In utero exposure to higher maternal AUCglu was associated with lower offspring blood DNAm levels at cg00967989 located in FSD1L gene (β = − 0.0267, P = 2.13 × 10–8) in adjusted linear regression mixed models. Our study also reports other CpG sites for which DNAm levels were suggestively associated (P < 1.0 × 10–5) with in utero exposure to gestational hyperglycemia. Two of these (cg12140144 and cg07946633) were found in the promotor region of PRDM16 gene (β: − 0.0251, P = 4.37 × 10–07 and β: − 0.0206, P = 2.24 × 10–06, respectively). Conclusion Maternal hyperglycemia is associated with offspring DNAm longitudinally assessed from birth to 5 years of age.

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Epigenome-Wide Association Study of Maternal Hemoglobin A1c in Pregnancy and Cord Blood DNA Methylation

Cited by 6 publications

References 69 publications

Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies

Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies

Multigenerational diabetes mellitus

Maternal glycemia in pregnancy is longitudinally associated with blood DNAm variation at the FSD1L gene from birth to 5 years of age

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