Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies
Elmar Tobi
(1)
,
Diana Juvinao-Quintero
(2)
,
Justiina Ronkainen
(3)
,
Raffael Ott
(4, 5)
,
Rossella Alfano
(6)
,
Mickaël Canouil
(7)
,
Madelon Geurtsen
(8, 1)
,
Amna Khamis
(7, 9)
,
Leanne Küpers
(8, 1)
,
Ives Lim
(10, 11)
,
Patrice Perron
(12, 13)
,
Giancarlo Pesce
(14, 15)
,
Johanna Tuhkanen
(16)
,
Anne Starling
(17, 18)
,
Toby Andrew
(9)
,
Elisabeth Binder
(19, 20)
,
Robert Caiazzo
(21)
,
Jerry Chan
(22, 23)
,
Romy Gaillard
(1, 9)
,
Peter Gluckman
(11, 24)
,
Elina Keikkala
(25, 26)
,
Neerja Karnani
(27, 11, 28)
,
Sanna Mustaniemi
(25, 26)
,
Tim Nawrot
(6)
,
François Pattou
(21)
,
Michelle Plusquin
(6)
,
Violeta Raverdy
(21)
,
Kok Hian Tan
(23, 22)
,
Evangelia Tzala
(9)
,
Katri Raikkonen
(29)
,
Christiane Winkler
(4, 5)
,
Anette-G. Ziegler
(4, 5)
,
Isabella Annesi-Maesano
(30)
,
Luigi Bouchard
(12, 31)
,
Yap-Seng Chong
(28, 32)
,
Dana Dabelea
(17, 18)
,
Janine F Felix
(8, 1)
,
Barbara Heude
(33)
,
Vincent W.V. Jaddoe
(34, 1)
,
Jari Lahti
(29)
,
Brigitte Reimann
(6)
,
Marja Vääräsmäki
(26)
,
Amelie Bonnefond
(7, 9)
,
Philippe Froguel
(7, 9)
,
Sandra Hummel
(4, 5)
,
Eero Kajantie
(25, 26, 35, 29)
,
Marjo-Riita Jarvelin
(26, 9, 36)
,
Régine P. M. Steegers-Theunissen
(1)
,
Caitlin G. Howe
(37)
,
Marie-France Hivert
(38, 39)
,
Sylvain Sebert
(26)
1
Erasmus MC -
Erasmus University Medical Center [Rotterdam]
2 Harvard Pilgrim Health Care Institute
3 University of Oulu [Finland] = Oulun yliopisto [Suomi] = Université d'Oulu [Finlande]
4 HMGU - 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 Medical Campus [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 OUH, OYKS, OYS - Oulu University Central Hospital [Finland] = Oulun yliopistollinen keskussairaala [Suomi] = Oulun yliopistollinen sairaala [Suomi]
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 Singapore Institute for Clinical Sciences (SICS)
33 CRESS (U1153 / UMR_A 1125) - Centre for Research in Epidemiology and Statistics | Centre de Recherche Épidémiologie et Statistiques
34 The Generation R Study Group
35 NMBU - Norwegian University of Life Sciences
36 Brunel University London [Uxbridge]
37 Geisel School of Medicine at Dartmouth
38 HMS - Harvard Medical School [Boston]
39 Massachusetts General Hospital [Boston]
2 Harvard Pilgrim Health Care Institute
3 University of Oulu [Finland] = Oulun yliopisto [Suomi] = Université d'Oulu [Finlande]
4 HMGU - 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 Medical Campus [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 OUH, OYKS, OYS - Oulu University Central Hospital [Finland] = Oulun yliopistollinen keskussairaala [Suomi] = Oulun yliopistollinen sairaala [Suomi]
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 Singapore Institute for Clinical Sciences (SICS)
33 CRESS (U1153 / UMR_A 1125) - Centre for Research in Epidemiology and Statistics | Centre de Recherche Épidémiologie et Statistiques
34 The Generation R Study Group
35 NMBU - Norwegian University of Life Sciences
36 Brunel University London [Uxbridge]
37 Geisel School of Medicine at Dartmouth
38 HMS - Harvard Medical School [Boston]
39 Massachusetts General Hospital [Boston]
Elmar Tobi
- Fonction : Auteur
- PersonId : 827502
- ORCID : 0000-0002-1378-3687
Justiina Ronkainen
- Fonction : Auteur
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- ORCID : 0000-0001-7375-8099
Mickaël Canouil
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Amna Khamis
- Fonction : Auteur
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- ORCID : 0000-0003-1709-304X
Giancarlo Pesce
- Fonction : Auteur
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- ORCID : 0000-0003-4925-6325
Elisabeth Binder
- Fonction : Auteur
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Romy Gaillard
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Peter Gluckman
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Neerja Karnani
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- ORCID : 0000-0002-5301-409X
François Pattou
- Fonction : Auteur
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- ORCID : 0000-0001-8388-3766
- IdRef : 074750364
Anette-G. Ziegler
- Fonction : Auteur
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- ORCID : 0000-0002-6290-5548
Isabella Annesi-Maesano
- Fonction : Auteur
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- IdHAL : isabella-annesi-maesano
- ORCID : 0000-0002-6340-9300
- IdRef : 123241847
Luigi Bouchard
- Fonction : Auteur
- PersonId : 1214297
- ORCID : 0000-0002-7852-0722
Yap-Seng Chong
- Fonction : Auteur
- PersonId : 1372053
- ORCID : 0000-0002-7232-8473
Barbara Heude
- Fonction : Auteur
- PersonId : 739512
- IdHAL : barbaraheude
- ORCID : 0000-0002-1565-1629
- IdRef : 083324593
Vincent W.V. Jaddoe
- Fonction : Auteur
- PersonId : 1214296
- ORCID : 0000-0003-2939-0041
Jari Lahti
- Fonction : Auteur
- PersonId : 775392
- ORCID : 0000-0002-4310-5297
Marja Vääräsmäki
- Fonction : Auteur
- PersonId : 827317
- ORCID : 0000-0002-8234-4434
Amelie Bonnefond
- Fonction : Auteur
- PersonId : 1305499
- IdHAL : amelie-bonnefond
- ORCID : 0000-0001-9976-3005
Philippe Froguel
- Fonction : Auteur
- PersonId : 1315149
- ORCID : 0000-0003-2972-0784
Sandra Hummel
- Fonction : Auteur
- PersonId : 827318
- ORCID : 0000-0001-6554-5974
Eero Kajantie
- Fonction : Auteur
- PersonId : 775395
- ORCID : 0000-0001-7081-8391
Marie-France Hivert
- Fonction : Auteur
- PersonId : 773567
- ORCID : 0000-0001-7752-2585
Résumé
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.