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Pediatrics

Genetic variation, intrauterine growth, and adverse pregnancy conditions predict leptin gene DNA methylation in blood at birth and 12 months of age

International Journal of Obesity volume 44, pages 45–56 (2020)Cite this article

Subjects

Abstract

Background

Leptin regulates satiety and energy homoeostasis, and plays a key role in placentation in pregnancy. Previous studies have demonstrated regulation of leptin gene (LEP) expression and/or methylation in placenta and cord blood in association with early life exposures, but most have been small and have not considered the influence of genetic variation. Here, we investigated the relationship between maternal factors in pregnancy, infant anthropometry and LEP genetic variation with LEP promoter methylation at birth and 12 months of age.

Methods

LEP methylation was measured in cord (n = 877) and 12-month (n = 734) blood in the Barwon Infant Study, a population-based pre-birth cohort. Infant adiposity at birth and 12-months was measured as triceps and subscapular skinfold thickness. Cross-sectional regression tested associations of methylation with pregnancy and anthropometry measures, while longitudinal regression tested if birth anthropometry predicted 12-month LEP methylation levels.

Results

Male infants had lower LEP methylation in cord blood (−2.07% average methylation, 95% CI (−2.92, −1.22), p < 0.001). Genetic variation strongly influenced DNA methylation at a single CpG site, which was also negatively associated with birth weight (r = −0.10, p = 0.003). Pre-eclampsia was associated with lower cord blood methylation at another CpG site (−6.06%, 95% CI (−10.70, −1.42), p = 0.01). Gestational diabetes was more modestly associated with methylation at two other CpG units. Adiposity at birth was associated with 12-month LEP methylation, modified by rs41457646 genotype. There was no association of LEP methylation with 12-month anthropometric measures.

Conclusions

Infant sex, weight, genetic variation, and exposure to pre-eclampsia and gestational diabetes, are associated with LEP methylation in cord blood. Infant adiposity at birth predicts 12-month blood LEP methylation in a genotype-dependent manner. These findings are consistent with genetics and anthropometry driving altered LEP epigenetic profile and expression in infancy. Further work is required to confirm this and to determine the long-term impact of altered LEP methylation on health.

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Data and code availability

The data and code used in this analysis are available upon reasonable request.

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Acknowledgements

We thank QIMR Berghofer Medical Research Institute and the Erasmus MC University Medical Center for their role in coordinating and performing the genotyping of BIS samples. The establishment work and infrastructure for the BIS was provided by the Murdoch Children’s Research Institute, Deakin University and Barwon Health. Subsequent funding was secured from the National Health and Medical Research Council of Australia, The Jack Brockhoff Foundation, the Scobie Trust, the Shane O’Brien Memorial Asthma Foundation, the Our Women’s Our Children’s Fund Raising Committee Barwon Health, The Shepherd Foundation, the Rotary Club of Geelong, the Ilhan Food Allergy Foundation, GMHBA Limited and the Percy Baxter Charitable Trust, Perpetual Trustees. In-kind support was provided by the Cotton On Foundation and CreativeForce. The study sponsors were not involved in the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication. Research at Murdoch Children’s Research Institute is supported by the Victorian Government's Operational Infrastructure Support Program. This work was also supported by a Research Training Program Stipend through University of Melbourne [to TM], NHMRC Senior Research Fellowships [APP1008396 to ALP; APP1045161 to RS]; and an NHMRC Dementia Research Leader Fellowship [APP1135727 to JR].

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Authors and Affiliations

  1. Murdoch Children’s Research Institute, Parkville, VIC, Australia

    Toby Mansell, Anne-Louise Ponsonby, Fiona Collier, David Burgner, Peter Vuillermin, Katherine Lange, Joanne Ryan, Richard Saffery, Peter Vuillermin, Anne-Louise Ponsonby, John Carlin, Katie Allen, Mimi Tang, Richard Saffery, Sarath Ranganathan, David Burgner, Terry Dwyer & Kim Jachno

  2. Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia

    Toby Mansell, Anne-Louise Ponsonby, David Burgner, Katherine Lange, Richard Saffery, Anne-Louise Ponsonby, Richard Saffery & David Burgner

  3. The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia

    Anne-Louise Ponsonby & Anne-Louise Ponsonby

  4. School of Medicine, Deakin University, Geelong, VIC, Australia

    Fiona Collier, Peter Vuillermin & Peter Vuillermin

  5. Child Health Research Unit, Barwon Health, Geelong, VIC, Australia

    Fiona Collier, Peter Vuillermin & Peter Vuillermin

  6. Department of Paediatrics, Monash University, Clayton, VIC, Australia

    David Burgner & David Burgner

  7. Department of Epidemiology and Preventative Medicine, Monash University, Clayton, VIC, Australia

    Joanne Ryan

  8. George Institute for Global Health, Sydney, NSW, Australia

    Terry Dwyer

  9. Queensland Children’s Medical Research Institute, University of Queensland, Brisbane, QLD, Australia

    Peter Sly

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Barwon Infant Study Investigator Team

  • Peter Vuillermin
  • , Anne-Louise Ponsonby
  • , John Carlin
  • , Katie Allen
  • , Mimi Tang
  • , Richard Saffery
  • , Sarath Ranganathan
  • , David Burgner
  • , Terry Dwyer
  • , Kim Jachno
  •  & Peter Sly

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Correspondence to Richard Saffery.

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Mansell, T., Ponsonby, AL., Collier, F. et al. Genetic variation, intrauterine growth, and adverse pregnancy conditions predict leptin gene DNA methylation in blood at birth and 12 months of age. Int J Obes 44, 45–56 (2020). https://doi.org/10.1038/s41366-019-0472-3

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