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

Elmar W. Tobi; Diana L. Juvinao-Quintero; Justiina Ronkainen; Raffael Ott; Rossella Alfano; Mickaël Canouil; Madelon L. Geurtsen; Amna Khamis; Leanne K. Küpers; Ives Y. Lim; Patrice Perron; Giancarlo Pesce; Johanna Tuhkanen; Anne P. Starling; Toby Andrew; Elisabeth Binder; Robert Caiazzo; Jerry K.Y. Chan; Romy Gaillard; Peter D. Gluckman; Elina Keikkala; Neerja Karnani; Sanna Mustaniemi; Tim S. Nawrot; François Pattou; Michelle Plusquin; Violeta Raverdy; Kok Hian Tan; Evangelia Tzala; Katri Raikkonen; Christiane Winkler; Anette G. Ziegler; Isabella Annesi-Maesano; Luigi Bouchard; Yap Seng Chong; Dana Dabelea; Janine F. Felix; Barbara Heude; Vincent W.V. Jaddoe; Jari Lahti; Brigitte Reimann; Marja Vääräsmäki; Amélie Bonnefond; Philippe Froguel; Sandra Hummel; Eero Kajantie; Marjo Riita Jarvelin; Regine P.M. Steegers-Theunissen; Caitlin G. Howe; Marie France Hivert; Sylvain Sebert

doi:10.2337/dc21-1701

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

Elmar W. Tobi^*, Diana L. Juvinao-Quintero, Justiina Ronkainen, Raffael Ott, Rossella Alfano, Mickaël Canouil, Madelon L. Geurtsen, Amna Khamis, Leanne K. Küpers, Ives Y. Lim, Patrice Perron, Giancarlo Pesce, Johanna Tuhkanen, Anne P. Starling, Toby Andrew, Elisabeth Binder, Robert Caiazzo, Jerry K.Y. Chan, Romy Gaillard, Peter D. GluckmanElina Keikkala, Neerja Karnani, Sanna Mustaniemi, Tim S. Nawrot, François Pattou, Michelle Plusquin, Violeta Raverdy, Kok Hian Tan, Evangelia Tzala, Katri Raikkonen, Christiane Winkler, Anette G. Ziegler, Isabella Annesi-Maesano, Luigi Bouchard, Yap Seng Chong, Dana Dabelea, Janine F. Felix, Barbara Heude, Vincent W.V. Jaddoe, Jari Lahti, Brigitte Reimann, Marja Vääräsmäki, Amélie Bonnefond, Philippe Froguel, Sandra Hummel, Eero Kajantie, Marjo Riita Jarvelin, Regine P.M. Steegers-Theunissen, Caitlin G. Howe, Marie France Hivert, Sylvain Sebert

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

30 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	614-623
Number of pages	10
Journal	Diabetes Care
Volume	45
Issue number	3
DOIs	https://doi.org/10.2337/dc21-1701
Publication status	Published - 1 Mar 2022

Bibliographical note

Funding Information:
E.W.T. was supported by a VENI grant from the Netherlands Organization for Scientific Research (91617128). This work was funded by the Joint Programming Initiative – A Healthy Diet for a Healthy Life (JPI HDHL) (proposal number 655). In the U.K. it is jointly funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (grant MR/ S03658X/1), in Spain by Instituto de Salud Carlos III (PCI2018-093147), in Germany by the German Federal Ministry of Education and Research (FKZ 01EA1905), in the Netherlands by ZonMw (529051023), and in France by French National Research Agency (ANR18-HDHL-0003-05). J.R. and S.S. received funding from the Healthy Diet for a Healthy Life (JPI HDHL) (PREcisE proposal no. 655) and the European Union’s Horizon 2020 research and innovation program under grant agreement nos. 733206 (LifeCycle), 824989 (EUCAN-Connect), 874739 (Longitools), and 848158 (EarlyCause). Information regarding funding for the contributing cohorts can be found in Supplementary Material.

Funding Information:
Acknowledgments. The authors thank the participants of the precision nutri-Epigenetic approach to tackle the PRECISion nutri-Epigenetic approach to tackle the mother-to-child transmission of impaired glucose metabolism (PREcisE) project for interesting discussion and feedback. Duality of Interest. N.K. and Y.S.C. are part of an academic consortium that has received research funding from Abbott Nutrition, Nestec, and Danone. Y.S.C. has received reimbursement for speaking at conferences sponsored by companies selling nutritional products. No other potential conflicts of interest relevant to this article were reported.

Funding Information:
These parties did not have any role in this research, the content of the manuscript, or the decision to publish. Funding. E.W.T. was supported by a VENI grant from the Netherlands Organization for Scientific Research (91617128). This work was funded by the Joint Programming Initiative – A Healthy Diet for a Healthy Life (JPI HDHL) (proposal number 655). In the U.K. it is jointly funded by the Medical Research Council and the Biotechnology and

Publisher Copyright:
© 2022, by the American Diabetes Association. All rights reserved.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.2337/dc21-1701

Cite this

Tobi, E. W., Juvinao-Quintero, D. L., Ronkainen, J., Ott, R., Alfano, R., Canouil, M., Geurtsen, M. L., Khamis, A., Küpers, L. K., Lim, I. Y., Perron, P., Pesce, G., Tuhkanen, J., Starling, A. P., Andrew, T., Binder, E., Caiazzo, R., Chan, J. K. Y., Gaillard, R., ... Sebert, S. (2022). Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies. Diabetes Care, 45(3), 614-623. https://doi.org/10.2337/dc21-1701

@article{cce29d3b2f79431e801832152261f2ec,

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

abstract = "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.",

author = "Tobi, {Elmar W.} and Juvinao-Quintero, {Diana L.} and Justiina Ronkainen and Raffael Ott and Rossella Alfano and Micka{\"e}l Canouil and Geurtsen, {Madelon L.} and Amna Khamis and K{\"u}pers, {Leanne K.} and Lim, {Ives Y.} and Patrice Perron and Giancarlo Pesce and Johanna Tuhkanen and Starling, {Anne P.} and Toby Andrew and Elisabeth Binder and Robert Caiazzo and Chan, {Jerry K.Y.} and Romy Gaillard and Gluckman, {Peter D.} and Elina Keikkala and Neerja Karnani and Sanna Mustaniemi and Nawrot, {Tim S.} and Fran{\c c}ois Pattou and Michelle Plusquin and Violeta Raverdy and Tan, {Kok Hian} and Evangelia Tzala and Katri Raikkonen and Christiane Winkler and Ziegler, {Anette G.} and Isabella Annesi-Maesano and Luigi Bouchard and Chong, {Yap Seng} and Dana Dabelea and Felix, {Janine F.} and Barbara Heude and Jaddoe, {Vincent W.V.} and Jari Lahti and Brigitte Reimann and Marja V{\"a}{\"a}r{\"a}sm{\"a}ki and Am{\'e}lie Bonnefond and Philippe Froguel and Sandra Hummel and Eero Kajantie and Jarvelin, {Marjo Riita} and Steegers-Theunissen, {Regine P.M.} and Howe, {Caitlin G.} and Hivert, {Marie France} and Sylvain Sebert",

note = "Funding Information: E.W.T. was supported by a VENI grant from the Netherlands Organization for Scientific Research (91617128). This work was funded by the Joint Programming Initiative – A Healthy Diet for a Healthy Life (JPI HDHL) (proposal number 655). In the U.K. it is jointly funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (grant MR/ S03658X/1), in Spain by Instituto de Salud Carlos III (PCI2018-093147), in Germany by the German Federal Ministry of Education and Research (FKZ 01EA1905), in the Netherlands by ZonMw (529051023), and in France by French National Research Agency (ANR18-HDHL-0003-05). J.R. and S.S. received funding from the Healthy Diet for a Healthy Life (JPI HDHL) (PREcisE proposal no. 655) and the European Union{\textquoteright}s Horizon 2020 research and innovation program under grant agreement nos. 733206 (LifeCycle), 824989 (EUCAN-Connect), 874739 (Longitools), and 848158 (EarlyCause). Information regarding funding for the contributing cohorts can be found in Supplementary Material. Funding Information: Acknowledgments. The authors thank the participants of the precision nutri-Epigenetic approach to tackle the PRECISion nutri-Epigenetic approach to tackle the mother-to-child transmission of impaired glucose metabolism (PREcisE) project for interesting discussion and feedback. Duality of Interest. N.K. and Y.S.C. are part of an academic consortium that has received research funding from Abbott Nutrition, Nestec, and Danone. Y.S.C. has received reimbursement for speaking at conferences sponsored by companies selling nutritional products. No other potential conflicts of interest relevant to this article were reported. Funding Information: These parties did not have any role in this research, the content of the manuscript, or the decision to publish. Funding. E.W.T. was supported by a VENI grant from the Netherlands Organization for Scientific Research (91617128). This work was funded by the Joint Programming Initiative – A Healthy Diet for a Healthy Life (JPI HDHL) (proposal number 655). In the U.K. it is jointly funded by the Medical Research Council and the Biotechnology and Publisher Copyright: {\textcopyright} 2022, by the American Diabetes Association. All rights reserved.",

year = "2022",

month = mar,

day = "1",

doi = "10.2337/dc21-1701",

language = "English",

volume = "45",

pages = "614--623",

journal = "Diabetes Care",

issn = "1935-5548",

publisher = "American Diabetes Association Inc.",

number = "3",

}

Tobi, EW, Juvinao-Quintero, DL, Ronkainen, J, Ott, R, Alfano, R, Canouil, M, Geurtsen, ML, Khamis, A, Küpers, LK, Lim, IY, Perron, P, Pesce, G, Tuhkanen, J, Starling, AP, Andrew, T, Binder, E, Caiazzo, R, Chan, JKY, Gaillard, R, Gluckman, PD, Keikkala, E, Karnani, N, Mustaniemi, S, Nawrot, TS, Pattou, F, Plusquin, M, Raverdy, V, Tan, KH, Tzala, E, Raikkonen, K, Winkler, C, Ziegler, AG, Annesi-Maesano, I, Bouchard, L, Chong, YS, Dabelea, D, Felix, JF, Heude, B, Jaddoe, VWV, Lahti, J, Reimann, B, Vääräsmäki, M, Bonnefond, A, Froguel, P, Hummel, S, Kajantie, E, Jarvelin, MR, Steegers-Theunissen, RPM, Howe, CG, Hivert, MF & Sebert, S 2022, 'Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies', Diabetes Care, vol. 45, no. 3, pp. 614-623. https://doi.org/10.2337/dc21-1701

TY - JOUR

T1 - Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation

T2 - Meta-analyses of Epigenome-Wide Association Studies

AU - Tobi, Elmar W.

AU - Juvinao-Quintero, Diana L.

AU - Ronkainen, Justiina

AU - Ott, Raffael

AU - Alfano, Rossella

AU - Canouil, Mickaël

AU - Geurtsen, Madelon L.

AU - Khamis, Amna

AU - Küpers, Leanne K.

AU - Lim, Ives Y.

AU - Perron, Patrice

AU - Pesce, Giancarlo

AU - Tuhkanen, Johanna

AU - Starling, Anne P.

AU - Andrew, Toby

AU - Binder, Elisabeth

AU - Caiazzo, Robert

AU - Chan, Jerry K.Y.

AU - Gaillard, Romy

AU - Gluckman, Peter D.

AU - Keikkala, Elina

AU - Karnani, Neerja

AU - Mustaniemi, Sanna

AU - Nawrot, Tim S.

AU - Pattou, François

AU - Plusquin, Michelle

AU - Raverdy, Violeta

AU - Tan, Kok Hian

AU - Tzala, Evangelia

AU - Raikkonen, Katri

AU - Winkler, Christiane

AU - Ziegler, Anette G.

AU - Annesi-Maesano, Isabella

AU - Bouchard, Luigi

AU - Chong, Yap Seng

AU - Dabelea, Dana

AU - Felix, Janine F.

AU - Heude, Barbara

AU - Jaddoe, Vincent W.V.

AU - Lahti, Jari

AU - Reimann, Brigitte

AU - Vääräsmäki, Marja

AU - Bonnefond, Amélie

AU - Froguel, Philippe

AU - Hummel, Sandra

AU - Kajantie, Eero

AU - Jarvelin, Marjo Riita

AU - Steegers-Theunissen, Regine P.M.

AU - Howe, Caitlin G.

AU - Hivert, Marie France

AU - Sebert, Sylvain

N1 - Funding Information: E.W.T. was supported by a VENI grant from the Netherlands Organization for Scientific Research (91617128). This work was funded by the Joint Programming Initiative – A Healthy Diet for a Healthy Life (JPI HDHL) (proposal number 655). In the U.K. it is jointly funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (grant MR/ S03658X/1), in Spain by Instituto de Salud Carlos III (PCI2018-093147), in Germany by the German Federal Ministry of Education and Research (FKZ 01EA1905), in the Netherlands by ZonMw (529051023), and in France by French National Research Agency (ANR18-HDHL-0003-05). J.R. and S.S. received funding from the Healthy Diet for a Healthy Life (JPI HDHL) (PREcisE proposal no. 655) and the European Union’s Horizon 2020 research and innovation program under grant agreement nos. 733206 (LifeCycle), 824989 (EUCAN-Connect), 874739 (Longitools), and 848158 (EarlyCause). Information regarding funding for the contributing cohorts can be found in Supplementary Material. Funding Information: Acknowledgments. The authors thank the participants of the precision nutri-Epigenetic approach to tackle the PRECISion nutri-Epigenetic approach to tackle the mother-to-child transmission of impaired glucose metabolism (PREcisE) project for interesting discussion and feedback. Duality of Interest. N.K. and Y.S.C. are part of an academic consortium that has received research funding from Abbott Nutrition, Nestec, and Danone. Y.S.C. has received reimbursement for speaking at conferences sponsored by companies selling nutritional products. No other potential conflicts of interest relevant to this article were reported. Funding Information: These parties did not have any role in this research, the content of the manuscript, or the decision to publish. Funding. E.W.T. was supported by a VENI grant from the Netherlands Organization for Scientific Research (91617128). This work was funded by the Joint Programming Initiative – A Healthy Diet for a Healthy Life (JPI HDHL) (proposal number 655). In the U.K. it is jointly funded by the Medical Research Council and the Biotechnology and Publisher Copyright: © 2022, by the American Diabetes Association. All rights reserved.

PY - 2022/3/1

Y1 - 2022/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85125882017&partnerID=8YFLogxK

U2 - 10.2337/dc21-1701

DO - 10.2337/dc21-1701

M3 - Article

C2 - 35104326

AN - SCOPUS:85125882017

SN - 1935-5548

VL - 45

SP - 614

EP - 623

JO - Diabetes Care

JF - Diabetes Care

IS - 3

ER -

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

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this