Early-life determinants of hypoxia-inducible factor 3A gene (HIF3A) methylation

A birth cohort study

Toby Mansell, Anne Louise Ponsonby, Vania Januar, Boris Novakovic, Fiona Collier, David Burgner, Peter Vuillermin, Joanne Ryan, Richard Saffery, Barwon Infant Study Investigator Team

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: Methylation of the hypoxia-inducible factor 3α gene (HIF3A) has been linked to pregnancy exposures, infant adiposity and later BMI. Genetic variation influences HIF3A methylation levels and may modify these relationships. However, data in very early life are limited, particularly in association with adverse pregnancy outcomes. We investigated the relationship between maternal and gestational factors, infant anthropometry, genetic variation and HIF3A DNA methylation in the Barwon Infant Study, a population-based birth cohort. Methylation of two previously studied regions of HIF3A were tested in the cord blood mononuclear cells of 938 infants. Results: No compelling evidence was found of an association between birth weight, adiposity or maternal gestational diabetes with methylation at the most widely studied HIF3A region. Male sex (- 4.3%, p < 0.001) and pre-eclampsia (- 5.4%, p = 0.02) negatively associated with methylation at a second region of HIF3A; while positive associations were identified for gestational diabetes (4.8%, p = 0.01) and gestational age (1.2% increase per week, p < 0.001). HIF3A genetic variation also associated strongly with methylation at this region (p < 0.001). Conclusions: Pre- and perinatal factors impact HIF3A methylation, including pre-eclampsia. This provides evidence that specific pregnancy complications, previously linked to adverse outcomes for both mother and child, impact the infant epigenome in a molecular pathway critical to several vascular and metabolic conditions. Further work is required to understand the mechanisms and clinical relevance, particularly the differing effects of in utero exposure to gestational diabetes or pre-eclampsia.

Original languageEnglish
Article number96
Number of pages12
JournalClinical Epigenetics
Volume11
Issue number1
DOIs
Publication statusPublished - 1 Jul 2019

Keywords

  • DNA methylation
  • Gestational diabetes
  • HIF3A
  • Infant
  • Pre-eclampsia
  • Pregnancy
  • SNPs

Cite this

Mansell, T., Ponsonby, A. L., Januar, V., Novakovic, B., Collier, F., Burgner, D., ... Barwon Infant Study Investigator Team (2019). Early-life determinants of hypoxia-inducible factor 3A gene (HIF3A) methylation: A birth cohort study. Clinical Epigenetics, 11(1), [96]. https://doi.org/10.1186/s13148-019-0687-0
Mansell, Toby ; Ponsonby, Anne Louise ; Januar, Vania ; Novakovic, Boris ; Collier, Fiona ; Burgner, David ; Vuillermin, Peter ; Ryan, Joanne ; Saffery, Richard ; Barwon Infant Study Investigator Team. / Early-life determinants of hypoxia-inducible factor 3A gene (HIF3A) methylation : A birth cohort study. In: Clinical Epigenetics. 2019 ; Vol. 11, No. 1.
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title = "Early-life determinants of hypoxia-inducible factor 3A gene (HIF3A) methylation: A birth cohort study",
abstract = "Background: Methylation of the hypoxia-inducible factor 3α gene (HIF3A) has been linked to pregnancy exposures, infant adiposity and later BMI. Genetic variation influences HIF3A methylation levels and may modify these relationships. However, data in very early life are limited, particularly in association with adverse pregnancy outcomes. We investigated the relationship between maternal and gestational factors, infant anthropometry, genetic variation and HIF3A DNA methylation in the Barwon Infant Study, a population-based birth cohort. Methylation of two previously studied regions of HIF3A were tested in the cord blood mononuclear cells of 938 infants. Results: No compelling evidence was found of an association between birth weight, adiposity or maternal gestational diabetes with methylation at the most widely studied HIF3A region. Male sex (- 4.3{\%}, p < 0.001) and pre-eclampsia (- 5.4{\%}, p = 0.02) negatively associated with methylation at a second region of HIF3A; while positive associations were identified for gestational diabetes (4.8{\%}, p = 0.01) and gestational age (1.2{\%} increase per week, p < 0.001). HIF3A genetic variation also associated strongly with methylation at this region (p < 0.001). Conclusions: Pre- and perinatal factors impact HIF3A methylation, including pre-eclampsia. This provides evidence that specific pregnancy complications, previously linked to adverse outcomes for both mother and child, impact the infant epigenome in a molecular pathway critical to several vascular and metabolic conditions. Further work is required to understand the mechanisms and clinical relevance, particularly the differing effects of in utero exposure to gestational diabetes or pre-eclampsia.",
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author = "Toby Mansell and Ponsonby, {Anne Louise} and Vania Januar and Boris Novakovic and Fiona Collier and David Burgner and Peter Vuillermin and Joanne Ryan and Richard Saffery and {Barwon Infant Study Investigator Team} and John Carlin and Katie Allen and Mimi Tang and Sarath Ranganathan and Terry Dwyer and Kim Jachno and Peter Sly",
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Mansell, T, Ponsonby, AL, Januar, V, Novakovic, B, Collier, F, Burgner, D, Vuillermin, P, Ryan, J, Saffery, R & Barwon Infant Study Investigator Team 2019, 'Early-life determinants of hypoxia-inducible factor 3A gene (HIF3A) methylation: A birth cohort study', Clinical Epigenetics, vol. 11, no. 1, 96. https://doi.org/10.1186/s13148-019-0687-0

Early-life determinants of hypoxia-inducible factor 3A gene (HIF3A) methylation : A birth cohort study. / Mansell, Toby; Ponsonby, Anne Louise; Januar, Vania; Novakovic, Boris; Collier, Fiona; Burgner, David; Vuillermin, Peter; Ryan, Joanne; Saffery, Richard; Barwon Infant Study Investigator Team.

In: Clinical Epigenetics, Vol. 11, No. 1, 96, 01.07.2019.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Early-life determinants of hypoxia-inducible factor 3A gene (HIF3A) methylation

T2 - A birth cohort study

AU - Mansell, Toby

AU - Ponsonby, Anne Louise

AU - Januar, Vania

AU - Novakovic, Boris

AU - Collier, Fiona

AU - Burgner, David

AU - Vuillermin, Peter

AU - Ryan, Joanne

AU - Saffery, Richard

AU - Barwon Infant Study Investigator Team

AU - Carlin, John

AU - Allen, Katie

AU - Tang, Mimi

AU - Ranganathan, Sarath

AU - Dwyer, Terry

AU - Jachno, Kim

AU - Sly, Peter

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Background: Methylation of the hypoxia-inducible factor 3α gene (HIF3A) has been linked to pregnancy exposures, infant adiposity and later BMI. Genetic variation influences HIF3A methylation levels and may modify these relationships. However, data in very early life are limited, particularly in association with adverse pregnancy outcomes. We investigated the relationship between maternal and gestational factors, infant anthropometry, genetic variation and HIF3A DNA methylation in the Barwon Infant Study, a population-based birth cohort. Methylation of two previously studied regions of HIF3A were tested in the cord blood mononuclear cells of 938 infants. Results: No compelling evidence was found of an association between birth weight, adiposity or maternal gestational diabetes with methylation at the most widely studied HIF3A region. Male sex (- 4.3%, p < 0.001) and pre-eclampsia (- 5.4%, p = 0.02) negatively associated with methylation at a second region of HIF3A; while positive associations were identified for gestational diabetes (4.8%, p = 0.01) and gestational age (1.2% increase per week, p < 0.001). HIF3A genetic variation also associated strongly with methylation at this region (p < 0.001). Conclusions: Pre- and perinatal factors impact HIF3A methylation, including pre-eclampsia. This provides evidence that specific pregnancy complications, previously linked to adverse outcomes for both mother and child, impact the infant epigenome in a molecular pathway critical to several vascular and metabolic conditions. Further work is required to understand the mechanisms and clinical relevance, particularly the differing effects of in utero exposure to gestational diabetes or pre-eclampsia.

AB - Background: Methylation of the hypoxia-inducible factor 3α gene (HIF3A) has been linked to pregnancy exposures, infant adiposity and later BMI. Genetic variation influences HIF3A methylation levels and may modify these relationships. However, data in very early life are limited, particularly in association with adverse pregnancy outcomes. We investigated the relationship between maternal and gestational factors, infant anthropometry, genetic variation and HIF3A DNA methylation in the Barwon Infant Study, a population-based birth cohort. Methylation of two previously studied regions of HIF3A were tested in the cord blood mononuclear cells of 938 infants. Results: No compelling evidence was found of an association between birth weight, adiposity or maternal gestational diabetes with methylation at the most widely studied HIF3A region. Male sex (- 4.3%, p < 0.001) and pre-eclampsia (- 5.4%, p = 0.02) negatively associated with methylation at a second region of HIF3A; while positive associations were identified for gestational diabetes (4.8%, p = 0.01) and gestational age (1.2% increase per week, p < 0.001). HIF3A genetic variation also associated strongly with methylation at this region (p < 0.001). Conclusions: Pre- and perinatal factors impact HIF3A methylation, including pre-eclampsia. This provides evidence that specific pregnancy complications, previously linked to adverse outcomes for both mother and child, impact the infant epigenome in a molecular pathway critical to several vascular and metabolic conditions. Further work is required to understand the mechanisms and clinical relevance, particularly the differing effects of in utero exposure to gestational diabetes or pre-eclampsia.

KW - DNA methylation

KW - Gestational diabetes

KW - HIF3A

KW - Infant

KW - Pre-eclampsia

KW - Pregnancy

KW - SNPs

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