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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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  1. Kopelman P. Health risks associated with overweight and obesity. Obes Rev. 2007;8:13–7.

    Article  Google Scholar 

  2. WHO. Report of a WHO Consultation on Obesity. Obesity-preventing and managing the global epidemic. WHO Technical Report Series, 894. 1997.

  3. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395:763.

    Article  CAS  Google Scholar 

  4. Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL, et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411:480.

    Article  CAS  Google Scholar 

  5. Adan R, Tiesjema B, Hillebrand J, La Fleur S, Kas M, De Krom M. The MC4 receptor and control of appetite. Br J Pharmacol. 2006;149:815–27.

    Article  CAS  Google Scholar 

  6. Green ED, Maffei M, Braden VV, Proenca R, DeSilva U, Zhang Y, et al. The human obese (OB) gene: RNA expression pattern and mapping on the physical, cytogenetic, and genetic maps of chromosome 7. Genome Res. 1995;5:5–12.

    Article  CAS  Google Scholar 

  7. Hoggard N, Haggarty P, Thomas L, Lea R. Leptin expression in placental and fetal tissues: does leptin have a functional role? Biochem Soc Trans 2001;29:57–63.

  8. Garcia-Cardona M, Huang F, García-Vivas JM, Lopez-Camarillo C, Del Rio Navarro B, Olivos EN, et al. DNA methylation of leptin and adiponectin promoters in children is reduced by the combined presence of obesity and insulin resistance. Int J Obes. 2014;38:1457.

    Article  CAS  Google Scholar 

  9. Lesseur C, Armstrong DA, Paquette AG, Koestler DC, Padbury JF, Marsit CJ. Tissue-specific Leptin promoter DNA methylation is associated with maternal and infant perinatal factors. Mol Cell Endocrinol. 2013;381:160–7.

    Article  CAS  Google Scholar 

  10. Mansell T, Ponsonby A-L, Collier F, Burgner D, Vuillermin P, Lange K, 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. 2019;44:1–12.

  11. Vuillermin P, Saffery R, Allen KJ, Carlin JB, Tang ML, Ranganathan S, et al. Cohort Profile: the Barwon Infant Study. Int J Epidemiol. 2015;44:1148–60.

  12. Margulies L, Horlick M, Thornton JC, Wang J, Ioannidou E, Heymsfield SB. Reproducibility of pediatric whole body bone and body composition measures by dual-energy X-ray absorptiometry using the GE Lunar Prodigy. J Clin Densitom. 2005;8:298–304.

    Article  Google Scholar 

  13. Pink B. Socio-economic indexes for areas (SEIFA) 2011. Canberra: Australian Bureau of Statistics; 2013.

    Google Scholar 

  14. Mansell T, Ponsonby A-L, Januar V, Novakovic B, Collier F, Burgner D, et al. Early-life determinants of hypoxia-inducible factor 3A gene (HIF3A) methylation: a birth cohort study. Clin Epigenetics. 2019;11:96.

    Article  Google Scholar 

  15. Vidmar S, Carlin J, Hesketh K, Cole T. Standardizing anthropometric measures in children and adolescents with new functions for egen. Stata J. 2004;4:50–5.

    Article  Google Scholar 

  16. McCloskey K, Ponsonby A-L, Collier F, Allen K, Tang MLK, Carlin JB, et al. The association between higher maternal pre-pregnancy body mass index and increased birth weight, adiposity and inflammation in the newborn. Pediatr Obes. 2018;13:46–53.

    Article  CAS  Google Scholar 

  17. Collier FM, Tang ML, Martino D, Saffery R, Carlin J, Jachno K, et al. The ontogeny of naïve and regulatory CD4+ T‐cell subsets during the first postnatal year: a cohort study. Clin Transl Immunol. 2015;4:e34.

    Article  Google Scholar 

  18. Jiang Y, Wilk J, Borecki I, Williamson S, DeStefano A, Xu G, et al. Common variants in the 5′ region of the leptin gene are associated with body mass index in men from the National Heart, Lung, and Blood Institute Family Heart Study. Am J Hum Genet. 2004;75:220–30.

    Article  CAS  Google Scholar 

  19. Marcello MA, Calixto AR, de Almeida JFM, Martins MB, Cunha LL, Cavalari CAA, et al. Polymorphism in LEP and LEPR may modify leptin levels and represent risk factors for thyroid cancer. Int J Endocrinol. 2015;2015:1–8.

  20. Altshuler DM, Gibbs RA, Peltonen L, Altshuler DM, Gibbs RA, Peltonen L, et al. Integrating common and rare genetic variation in diverse human populations. Nature. 2010;467:52–8.

    Article  CAS  Google Scholar 

  21. Houde A-A, Légaré C, Hould F-S, Lebel S, Marceau P, Tchernof A, et al. Cross-tissue comparisons of leptin and adiponectin: DNA methylation profiles. Adipocyte. 2014;3:132–40.

    Article  CAS  Google Scholar 

  22. Melzner I, Scott V, Dorsch K, Fischer P, Wabitsch M, Brüderlein S, et al. Leptin gene expression in human preadipocytes is switched on by maturation-induced demethylation of distinct CpGs in its proximal promoter. J Biol Chem. 2002;277:45420–7.

    Article  CAS  Google Scholar 

  23. Houde AA, Legare C, Biron S, Lescelleur O, Biertho L, Marceau S, et al. Leptin and adiponectin DNA methylation levels in adipose tissues and blood cells are associated with BMI, waist girth and LDL-cholesterol levels in severely obese men and women. BMC Med Genet. 2015;16:29.

    Article  Google Scholar 

  24. Bennett CE, Nsengimana J, Bostock JA, Cymbalista C, Futers TS, Knight BL, et al. CCAAT/enhancer binding protein α, β and δ gene variants: associations with obesity related phenotypes in the Leeds Family Study. Diab Vasc Dis Res. 2010;7:195–203.

    Article  Google Scholar 

  25. Lannergård A, Friman G, Ewald U, Lind L, Larsson A. Serum amyloid A (SAA) protein and high-sensitivity C-reactive protein (hsCRP) in healthy newborn infants and healthy young through elderly adults. Acta Paediatr. 2005;94:1198–202.

    Article  Google Scholar 

  26. Ito Y, Banno R, Shibata M, Adachi K, Hagimoto S, Hagiwara D, et al. GABA type B receptor signaling in proopiomelanocortin neurons protects against obesity, insulin resistance, and hypothalamic inflammation in male mice on a high-fat diet. J Neurosci. 2013;33:17166–73.

    Article  CAS  Google Scholar 

  27. Clegg DJ, Riedy CA, Smith KAB, Benoit SC, Woods SC. Differential sensitivity to central leptin and insulin in male and female rats. Diabetes. 2003;52:682–7.

    Article  CAS  Google Scholar 

  28. Shi H, Strader AD, Sorrell JE, Chambers JB, Woods SC, Seeley RJ. Sexually different actions of leptin in proopiomelanocortin neurons to regulate glucose homeostasis. Am J Physiol-Endocrinol Metab. 2008;294:E630–9.

  29. Chowen JA, Freire-Regatillo A, Argente J. Neurobiological characteristics underlying metabolic differences between males and females. Prog Neurobiol. 2019;176:18–32.

    Article  CAS  Google Scholar 

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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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