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Article Dans Une Revue Diabetes Care Année : 2022

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

1 Erasmus MC - Erasmus University Medical Center [Rotterdam]
2 Harvard Pilgrim Health Care Institute
3 University of Oulu
4 Helmholtz Zentrum München = German Research Center for Environmental Health
5 MRI TUM - Klinikum rechts der Isar
6 UHasselt - Hasselt University
7 EGENODIA (GI3M) - Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283
8 The Generation R Study Group
9 Imperial College London
10 A*STAR - Bioinformatics Institute
11 SICS - Singapore Institute for Clinical Sciences [Singapour]
12 UdeS - Université de Sherbrooke
13 Centre Hospitalier Universitaire de Sherbrooke
14 CESP - Centre de recherche en épidémiologie et santé des populations
15 EPAR - Epidemiology of Allergic and Respiratory Diseases Department [iPlesp]
16 TKK - TKK Helsinki University of Technology
17 CSPH - Colorado School of Public Health [Aurora, CO, USA]
18 University of Colorado Anschutz [Aurora]
19 Max Planck Institute of Psychiatry
20 Emory University School of Medicine
21 RTD - Recherche translationnelle sur le diabète - U 1190
22 KK Women's and Children's Hospital [Singapore]
23 Duke-NUS Medical School [Singapore]
24 Liggins Institute
25 FIHW - Finnish Institute for Health and Welfare
26 Oulu University Hospital [Oulu]
27 Bioinformatics Institute [Singapore]
28 Yong Loo Lin School of Medicine [Singapore]
29 Faculty of Medecine [Helsinki]
30 IDESP - Institut Desbrest de santé publique
31 UQAC - Université du Québec à Chicoutimi
32 CRESS (U1153 / UMR_A 1125) - Centre for Research in Epidemiology and Statistics | Centre de Recherche Épidémiologie et Statistiques
33 NMBU - Norwegian University of Life Sciences
34 Brunel University London [Uxbridge]
35 Geisel School of Medicine at Dartmouth
36 HMS - Harvard Medical School [Boston]
37 Massachusetts General Hospital [Boston]
Justiina Ronkainen
Tim Nawrot
  • Fonction : Auteur
Jari Lahti
Marja Vääräsmäki


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.

Dates et versions

hal-03676276 , version 1 (23-05-2022)



Elmar Tobi, Diana Juvinao-Quintero, Justiina Ronkainen, Raffael Ott, Rossella Alfano, et al.. Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies. Diabetes Care, 2022, 45 (3), pp.614-623. ⟨10.2337/dc21-1701⟩. ⟨hal-03676276⟩
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