Maternal iron status in early pregnancy and DNA methylation in offspring: an epigenome-wide meta-analysis

Jazmin Taeubert Santacruz; P. de Prado‑Ber; M. L.  Geurtsen; Giulia Mancano; M. J.  Vermeulen; I. K. M.  Reiss; Doretta Caramaschi; J.  Sunyer; Gemma C Sharp; J.  Julvez; M. U.  Muckenthaler; Janin F.  Felix

doi:10.1186/s13148-022-01276-w

Maternal iron status in early pregnancy and DNA methylation in offspring: an epigenome-wide meta-analysis

Jazmin Taeubert Santacruz, P. de Prado‑Ber, M. L. Geurtsen, Giulia Mancano, M. J. Vermeulen, I. K. M. Reiss, Doretta Caramaschi, J. Sunyer, Gemma C Sharp, J. Julvez, M. U. Muckenthaler, Janin F. Felix^*

^*Corresponding author for this work

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Abstract

Background
Unbalanced iron homeostasis in pregnancy is associated with an increased risk of adverse birth and childhood health outcomes. DNA methylation has been suggested as a potential underlying mechanism linking environmental exposures such as micronutrient status during pregnancy with offspring health. We performed a meta-analysis on the association of maternal early-pregnancy serum ferritin concentrations, as a marker of body iron stores, and cord blood DNA methylation. We included 1286 mother–newborn pairs from two population-based prospective cohorts. Serum ferritin concentrations were measured in early pregnancy. DNA methylation was measured with the Infinium HumanMethylation450 BeadChip (Illumina). We examined epigenome-wide associations of maternal early-pregnancy serum ferritin and cord blood DNA methylation using robust linear regression analyses, with adjustment for confounders and performed fixed-effects meta-analyses. We additionally examined whether associations of any CpGs identified in cord blood persisted in the peripheral blood of older children and explored associations with other markers of maternal iron status. We also examined whether similar findings were present in the association of cord blood serum ferritin concentrations with cord blood DNA methylation.

Results
Maternal early-pregnancy serum ferritin concentrations were inversely associated with DNA methylation at two CpGs (cg02806645 and cg06322988) in PRR23A and one CpG (cg04468817) in PRSS22. Associations at two of these CpG sites persisted at each of the follow-up time points in childhood. Cord blood serum ferritin concentrations were not associated with cord blood DNA methylation levels at the three identified CpGs.

Conclusion
Maternal early-pregnancy serum ferritin concentrations were associated with lower cord blood DNA methylation levels at three CpGs and these associations partly persisted in older children. Further studies are needed to uncover the role of these CpGs in the underlying mechanisms of the associations of maternal iron status and offspring health outcomes.

Original language	English
Article number	59
Number of pages	12
Journal	Clinical Epigenetics
Volume	14
Issue number	1
Early online date	3 May 2022
DOIs	https://doi.org/10.1186/s13148-022-01276-w
Publication status	E-pub ahead of print - 3 May 2022

Bibliographical note

Funding Information:
Cohort-specific funding statements can be found in Additional file . Wellcome Trust, 217065/Z/19/Z, UK Medical Research Council Integrative Epidemiology Unit and the University of Bristol, MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5, MC_UU_12013_8, MC_UU_00011/1, MC_UU_00011/5, MC_UU_00011/6, Medical Research Council, MR/S009310/1 Joint Programming Initiative “A Healthy Diet for a Healthy Life”, MR/S036520/1, ZonMw the Netherlands no. 529051022 (NutriPROGRAM), no. 529051023 (PREcisE), UK Biotechnology and Biological Sciences Research Council, BB/I025751/1, BB/I025263/1, United States National Institute of Health, 5RO1AI121226-02, National Institute of Child and Human Development, R01HD068437, ErasmusMC, University Medical Center Rotterdam; the Netherlands Organization for Health Research and Development; the Dutch Ministry of Health, Welfare, and Sport; Netherlands Consortium for Healthy Aging, 050-060-810, Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, European Union’s Horizon 2020 research and innovation programme, 733206 (LifeCycle), 874739 (LongITools), 824989 (EUCAN-Connect), Deutscher Akademischer Austauschdienst, Dietmar Hopp Stiftung, Instituto de Salud Carlos III, Red INMA G03/176, CB06/02/0041, Miguel Servet-II contract CPII19/00015 (Co-funded by the European Social Fund “Investing in your future”) Spanish Ministry of Health, FIS-PI04/1436, FIS-PI08/1151 including FEDER funds, FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03-1615, MS13/00054, CP18/00018, Generalitat de Catalunya, CIRIT 1999SGR 00241, Fundació la Marató de TV3,090430, EU Commission, 261357-MeDALL: Mechanisms of the Development of ALLergy, European Research Council, 268479-BREATHE: BRain dEvelopment, Air polluTion ultrafine particles in scHool children.

Publisher Copyright:
© 2022, The Author(s).

Research Groups and Themes

ALSPAC

Keywords

DNA methylation
Iron metabolism
Differentially methylated regions
Epigenetics
Maternal serum ferritin

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Santacruz, J. T., de Prado‑Ber, P., Geurtsen, M. L., Mancano, G., Vermeulen, M. J., Reiss, I. K. M., Caramaschi, D., Sunyer, J., Sharp, G. C., Julvez, J., Muckenthaler, M. U., & Felix, J. F. (2022). Maternal iron status in early pregnancy and DNA methylation in offspring: an epigenome-wide meta-analysis. Clinical Epigenetics, 14(1), Article 59. Advance online publication. https://doi.org/10.1186/s13148-022-01276-w

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title = "Maternal iron status in early pregnancy and DNA methylation in offspring: an epigenome-wide meta-analysis",

abstract = "Background Unbalanced iron homeostasis in pregnancy is associated with an increased risk of adverse birth and childhood health outcomes. DNA methylation has been suggested as a potential underlying mechanism linking environmental exposures such as micronutrient status during pregnancy with offspring health. We performed a meta-analysis on the association of maternal early-pregnancy serum ferritin concentrations, as a marker of body iron stores, and cord blood DNA methylation. We included 1286 mother–newborn pairs from two population-based prospective cohorts. Serum ferritin concentrations were measured in early pregnancy. DNA methylation was measured with the Infinium HumanMethylation450 BeadChip (Illumina). We examined epigenome-wide associations of maternal early-pregnancy serum ferritin and cord blood DNA methylation using robust linear regression analyses, with adjustment for confounders and performed fixed-effects meta-analyses. We additionally examined whether associations of any CpGs identified in cord blood persisted in the peripheral blood of older children and explored associations with other markers of maternal iron status. We also examined whether similar findings were present in the association of cord blood serum ferritin concentrations with cord blood DNA methylation. Results Maternal early-pregnancy serum ferritin concentrations were inversely associated with DNA methylation at two CpGs (cg02806645 and cg06322988) in PRR23A and one CpG (cg04468817) in PRSS22. Associations at two of these CpG sites persisted at each of the follow-up time points in childhood. Cord blood serum ferritin concentrations were not associated with cord blood DNA methylation levels at the three identified CpGs. Conclusion Maternal early-pregnancy serum ferritin concentrations were associated with lower cord blood DNA methylation levels at three CpGs and these associations partly persisted in older children. Further studies are needed to uncover the role of these CpGs in the underlying mechanisms of the associations of maternal iron status and offspring health outcomes.",

keywords = "DNA methylation, Iron metabolism, Differentially methylated regions, Epigenetics, Maternal serum ferritin",

author = "Santacruz, \{Jazmin Taeubert\} and \{de Prado‑Ber\}, P. and Geurtsen, \{M. L.\} and Giulia Mancano and Vermeulen, \{M. J.\} and Reiss, \{I. K. M.\} and Doretta Caramaschi and J. Sunyer and Sharp, \{Gemma C\} and J. Julvez and Muckenthaler, \{M. U.\} and Felix, \{Janin F.\}",

note = "Funding Information: Cohort-specific funding statements can be found in Additional file . Wellcome Trust, 217065/Z/19/Z, UK Medical Research Council Integrative Epidemiology Unit and the University of Bristol, MC\_UU\_12013\_1, MC\_UU\_12013\_2, MC\_UU\_12013\_5, MC\_UU\_12013\_8, MC\_UU\_00011/1, MC\_UU\_00011/5, MC\_UU\_00011/6, Medical Research Council, MR/S009310/1 Joint Programming Initiative “A Healthy Diet for a Healthy Life”, MR/S036520/1, ZonMw the Netherlands no. 529051022 (NutriPROGRAM), no. 529051023 (PREcisE), UK Biotechnology and Biological Sciences Research Council, BB/I025751/1, BB/I025263/1, United States National Institute of Health, 5RO1AI121226-02, National Institute of Child and Human Development, R01HD068437, ErasmusMC, University Medical Center Rotterdam; the Netherlands Organization for Health Research and Development; the Dutch Ministry of Health, Welfare, and Sport; Netherlands Consortium for Healthy Aging, 050-060-810, Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, European Union{\textquoteright}s Horizon 2020 research and innovation programme, 733206 (LifeCycle), 874739 (LongITools), 824989 (EUCAN-Connect), Deutscher Akademischer Austauschdienst, Dietmar Hopp Stiftung, Instituto de Salud Carlos III, Red INMA G03/176, CB06/02/0041, Miguel Servet-II contract CPII19/00015 (Co-funded by the European Social Fund “Investing in your future”) Spanish Ministry of Health, FIS-PI04/1436, FIS-PI08/1151 including FEDER funds, FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03-1615, MS13/00054, CP18/00018, Generalitat de Catalunya, CIRIT 1999SGR 00241, Fundaci{\'o} la Marat{\'o} de TV3,090430, EU Commission, 261357-MeDALL: Mechanisms of the Development of ALLergy, European Research Council, 268479-BREATHE: BRain dEvelopment, Air polluTion ultrafine particles in scHool children. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = may,

day = "3",

doi = "10.1186/s13148-022-01276-w",

language = "English",

volume = "14",

journal = "Clinical Epigenetics",

issn = "1868-7075",

publisher = "BioMed Central Ltd",

number = "1",

}

TY - JOUR

T1 - Maternal iron status in early pregnancy and DNA methylation in offspring

T2 - an epigenome-wide meta-analysis

AU - Santacruz, Jazmin Taeubert

AU - de Prado‑Ber, P.

AU - Geurtsen, M. L.

AU - Mancano, Giulia

AU - Vermeulen, M. J.

AU - Reiss, I. K. M.

AU - Caramaschi, Doretta

AU - Sunyer, J.

AU - Sharp, Gemma C

AU - Julvez, J.

AU - Muckenthaler, M. U.

AU - Felix, Janin F.

N1 - Funding Information: Cohort-specific funding statements can be found in Additional file . Wellcome Trust, 217065/Z/19/Z, UK Medical Research Council Integrative Epidemiology Unit and the University of Bristol, MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5, MC_UU_12013_8, MC_UU_00011/1, MC_UU_00011/5, MC_UU_00011/6, Medical Research Council, MR/S009310/1 Joint Programming Initiative “A Healthy Diet for a Healthy Life”, MR/S036520/1, ZonMw the Netherlands no. 529051022 (NutriPROGRAM), no. 529051023 (PREcisE), UK Biotechnology and Biological Sciences Research Council, BB/I025751/1, BB/I025263/1, United States National Institute of Health, 5RO1AI121226-02, National Institute of Child and Human Development, R01HD068437, ErasmusMC, University Medical Center Rotterdam; the Netherlands Organization for Health Research and Development; the Dutch Ministry of Health, Welfare, and Sport; Netherlands Consortium for Healthy Aging, 050-060-810, Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, European Union’s Horizon 2020 research and innovation programme, 733206 (LifeCycle), 874739 (LongITools), 824989 (EUCAN-Connect), Deutscher Akademischer Austauschdienst, Dietmar Hopp Stiftung, Instituto de Salud Carlos III, Red INMA G03/176, CB06/02/0041, Miguel Servet-II contract CPII19/00015 (Co-funded by the European Social Fund “Investing in your future”) Spanish Ministry of Health, FIS-PI04/1436, FIS-PI08/1151 including FEDER funds, FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03-1615, MS13/00054, CP18/00018, Generalitat de Catalunya, CIRIT 1999SGR 00241, Fundació la Marató de TV3,090430, EU Commission, 261357-MeDALL: Mechanisms of the Development of ALLergy, European Research Council, 268479-BREATHE: BRain dEvelopment, Air polluTion ultrafine particles in scHool children. Publisher Copyright: © 2022, The Author(s).

PY - 2022/5/3

Y1 - 2022/5/3

N2 - Background Unbalanced iron homeostasis in pregnancy is associated with an increased risk of adverse birth and childhood health outcomes. DNA methylation has been suggested as a potential underlying mechanism linking environmental exposures such as micronutrient status during pregnancy with offspring health. We performed a meta-analysis on the association of maternal early-pregnancy serum ferritin concentrations, as a marker of body iron stores, and cord blood DNA methylation. We included 1286 mother–newborn pairs from two population-based prospective cohorts. Serum ferritin concentrations were measured in early pregnancy. DNA methylation was measured with the Infinium HumanMethylation450 BeadChip (Illumina). We examined epigenome-wide associations of maternal early-pregnancy serum ferritin and cord blood DNA methylation using robust linear regression analyses, with adjustment for confounders and performed fixed-effects meta-analyses. We additionally examined whether associations of any CpGs identified in cord blood persisted in the peripheral blood of older children and explored associations with other markers of maternal iron status. We also examined whether similar findings were present in the association of cord blood serum ferritin concentrations with cord blood DNA methylation. Results Maternal early-pregnancy serum ferritin concentrations were inversely associated with DNA methylation at two CpGs (cg02806645 and cg06322988) in PRR23A and one CpG (cg04468817) in PRSS22. Associations at two of these CpG sites persisted at each of the follow-up time points in childhood. Cord blood serum ferritin concentrations were not associated with cord blood DNA methylation levels at the three identified CpGs. Conclusion Maternal early-pregnancy serum ferritin concentrations were associated with lower cord blood DNA methylation levels at three CpGs and these associations partly persisted in older children. Further studies are needed to uncover the role of these CpGs in the underlying mechanisms of the associations of maternal iron status and offspring health outcomes.

AB - Background Unbalanced iron homeostasis in pregnancy is associated with an increased risk of adverse birth and childhood health outcomes. DNA methylation has been suggested as a potential underlying mechanism linking environmental exposures such as micronutrient status during pregnancy with offspring health. We performed a meta-analysis on the association of maternal early-pregnancy serum ferritin concentrations, as a marker of body iron stores, and cord blood DNA methylation. We included 1286 mother–newborn pairs from two population-based prospective cohorts. Serum ferritin concentrations were measured in early pregnancy. DNA methylation was measured with the Infinium HumanMethylation450 BeadChip (Illumina). We examined epigenome-wide associations of maternal early-pregnancy serum ferritin and cord blood DNA methylation using robust linear regression analyses, with adjustment for confounders and performed fixed-effects meta-analyses. We additionally examined whether associations of any CpGs identified in cord blood persisted in the peripheral blood of older children and explored associations with other markers of maternal iron status. We also examined whether similar findings were present in the association of cord blood serum ferritin concentrations with cord blood DNA methylation. Results Maternal early-pregnancy serum ferritin concentrations were inversely associated with DNA methylation at two CpGs (cg02806645 and cg06322988) in PRR23A and one CpG (cg04468817) in PRSS22. Associations at two of these CpG sites persisted at each of the follow-up time points in childhood. Cord blood serum ferritin concentrations were not associated with cord blood DNA methylation levels at the three identified CpGs. Conclusion Maternal early-pregnancy serum ferritin concentrations were associated with lower cord blood DNA methylation levels at three CpGs and these associations partly persisted in older children. Further studies are needed to uncover the role of these CpGs in the underlying mechanisms of the associations of maternal iron status and offspring health outcomes.

KW - DNA methylation

KW - Iron metabolism

KW - Differentially methylated regions

KW - Epigenetics

KW - Maternal serum ferritin

U2 - 10.1186/s13148-022-01276-w

DO - 10.1186/s13148-022-01276-w

M3 - Article (Academic Journal)

C2 - 35505416

SN - 1868-7075

VL - 14

JO - Clinical Epigenetics

JF - Clinical Epigenetics

IS - 1

M1 - 59

ER -

Maternal iron status in early pregnancy and DNA methylation in offspring: an epigenome-wide meta-analysis

Abstract

Bibliographical note

Research Groups and Themes

Keywords

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