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Methylation of the LEP gene promoter in blood at 12 months and BMI at 4 years of age—a population-based cohort study


Increasing evidence links epigenetic variation to anthropometric and metabolic measures. Leptin signalling regulates appetite and energy expenditure, and in pregnancy is important for nutrient supply to the foetus. Maternal metabolic health and foetal growth are linked to infant blood leptin gene (LEP) methylation, which has been cross-sectionally associated with adolescent obesity. Despite this, few studies have explored the relationship between infant LEP methylation and childhood anthropometry, or the impact of genetic variation on these relationships. Using a prospective birth cohort, we investigated whether blood LEP promoter methylation at birth and 12 months predicts weight and adiposity at 4-years. Locus-specific methylation data was analysed by partial correlation tests and multivariable linear regression. There was weak evidence of an association of birth LEP methylation with anthropometry measures at 4 years. Methylation at a specific site (cg19594666) at 12 months was inversely associated with 4-year weight (r = −0.11, p = 0.02) and body-mass index (BMI) (r = −0.13, p = 0.007), which persisted following adjustment for weight at birth and at 12 months. Neither association was influenced by genotype. We report the first evidence of an association between LEP methylation in infancy and childhood weight. Replication in additional cohorts is required to determine if this relationship persists.

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The data used for this analysis are available on reasonable request.

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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].

Barwon Infant Study Investigator Team

Barwon Infant Study Investigator Team, Peter Vuillermin1,4,5, Fiona Collier1,4,5, Anne-Louise Ponsonby1,2,3, John Carlin1,2, Katie Allen1,2, Mimi Tang1,2, Richard Saffery1,2, Sarath Ranganathan1,2, David Burgner1,2,6, Terry Dwyer1,8, Peter Sly9

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Correspondence to Richard Saffery.

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Members of the Barwon Infant Study Investigator Team are listed below Acknowledgements.

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Mansell, T., Ponsonby, AL., Collier, F. et al. Methylation of the LEP gene promoter in blood at 12 months and BMI at 4 years of age—a population-based cohort study. Int J Obes 44, 842–847 (2020).

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