Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pediatrics

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

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2

Data and code availability

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

References

  1. 1.

    Drake AJ, Reynolds RM. Impact of maternal obesity on offspring obesity and cardiometabolic disease risk. Reproduction. 2010;140:387–98.

    CAS  PubMed  Google Scholar 

  2. 2.

    West NA, Crume TL, Maligie MA, Dabelea D. Cardiovascular risk factors in children exposed to maternal diabetes in utero. Diabetologia. 2011;54:504–7.

    CAS  PubMed  Google Scholar 

  3. 3.

    Davis EF, Lazdam M, Lewandowski AJ, Worton SA, Kelly B, Kenworthy Y, et al. Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systematic review. Pediatrics. 2012;129:e1552–e61.

    PubMed  Google Scholar 

  4. 4.

    Smith CJ, Ryckman KK. Epigenetic and developmental influences on the risk of obesity, diabetes, and metabolic syndrome. Diabetes Metab Syndr Obes. 2015;8:295–302.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

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

    CAS  PubMed  Google Scholar 

  6. 6.

    Grattan DR, Ladyman SR, Augustine RA. Hormonal induction of leptin resistance during pregnancy. Physiol Behav. 2007;91:366–74.

    CAS  PubMed  Google Scholar 

  7. 7.

    Jansson N, Greenwood S, Johansson B, Powell T, Jansson T. Leptin stimulates the activity of the system A amino acid transporter in human placental villous fragments. J Clin Endocrinol Metab. 2003;88:1205–11.

    CAS  PubMed  Google Scholar 

  8. 8.

    Myers MG,Jr. Leibel RL, Seeley RJ, Schwartz MW. Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metab. 2010;21:643–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Briffa JF, McAinch AJ, Romano T, Wlodek ME, Hryciw DH. Leptin in pregnancy and development: a contributor to adulthood disease? Am J Physiol Endocrinol Metab. 2015;308:E335–50.

    CAS  PubMed  Google Scholar 

  10. 10.

    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.

    CAS  PubMed  Google Scholar 

  11. 11.

    Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau J-P, Bortoluzzi M-N, et al. The stomach is a source of leptin. Nature. 1998;394:790.

    CAS  PubMed  Google Scholar 

  12. 12.

    Hogg K, Robinson WP, Beristain AG. Activation of endocrine-related gene expression in placental choriocarcinoma cell lines following DNA methylation knock-down. Mol Hum Reprod. 2014;20:677–89.

    CAS  PubMed  Google Scholar 

  13. 13.

    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.

    CAS  PubMed  Google Scholar 

  14. 14.

    Iliopoulos D, Malizos KN, Tsezou A. Epigenetic regulation of leptin affects MMP-13 expression in osteoarthritic chondrocytes: possible molecular target for osteoarthritis therapeutic intervention. Ann Rheum Dis. 2007;66:1616–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Kadakia R, Zheng Y, Zhang Z, Zhang W, Hou L, Josefson JL. Maternal pre-pregnancy BMI downregulates neonatal cord blood LEP methylation. Pediatr Obes. 2017;12(S1):57–64.

    PubMed  Google Scholar 

  17. 17.

    Allard C, Desgagne V, Patenaude J, Lacroix M, Guillemette L, Battista MC, et al. Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns. Epigenetics. 2015;10:342–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Lesseur C, Armstrong DA, Paquette AG, Li Z, Padbury JF, Marsit CJ. Maternal obesity and gestational diabetes are associated with placental leptin DNA methylation. Am JObstet Gynecol. 2014;211:654.e1–9.

    CAS  Google Scholar 

  19. 19.

    Bouchard L, Thibault S, Guay SP, Santure M, Monpetit A, St-Pierre J, et al. Leptin gene epigenetic adaptation to impaired glucose metabolism during pregnancy. Diabetes Care. 2010;33:2436–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Hogg K, Blair JD, von Dadelszen P, Robinson WP. Hypomethylation of the LEP gene in placenta and elevated maternal leptin concentration in early onset pre-eclampsia. Mol Cell Endocrinol. 2013;367:64–73.

    CAS  PubMed  Google Scholar 

  21. 21.

    Xiang Y, Cheng Y, Li X, Li Q, Xu J, Zhang J, et al. Up-regulated expression and aberrant DNA methylation of LEP and SH3PXD2A in pre-eclampsia. PloS ONE. 2013;8:e59753.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Laivuori H, Gallaher M, Collura L, Crombleholme W, Markovic N, Rajakumar A, et al. Relationships between maternal plasma leptin, placental leptin mRNA and protein in normal pregnancy, pre-eclampsia and intrauterine growth restriction without pre-eclampsia. Mol Hum reprod. 2006;12:551–6.

    CAS  PubMed  Google Scholar 

  23. 23.

    Ødegård RA, Vatten LJ, Nilsen ST, Salvesen KÅ, Austgulen R. Umbilical cord plasma leptin is increased in preeclampsia. Am J Obstet Gynecol. 2002;186:427–32.

    PubMed  Google Scholar 

  24. 24.

    Ng EK, Leung TN, Tsui NB, Lau TK, Panesar NS, Chiu RW, et al. The concentration of circulating corticotropin-releasing hormone mRNA in maternal plasma is increased in preeclampsia. Clini Chem. 2003;49:727–31.

    CAS  Google Scholar 

  25. 25.

    Tian F-Y, Rifas-Shiman SL, Cardenas A, Baccarelli AA, DeMeo DL, Litonjua AA, et al. Maternal corticotropin-releasing hormone is associated with LEP DNA methylation at birth and in childhood: an epigenome-wide study in Project Viva. Int J Obes. 2018:1.

  26. 26.

    Wang Y-H, Xu X-X, Sun H, Han Y, Lei Z-F, Wang Y-C, et al. Cord blood leptin DNA methylation levels are associated with macrosomia during normal pregnancy. Pediatr Res. 2019;86:305–10.

    PubMed  Google Scholar 

  27. 27.

    Xu X, Yang X, Liu Z, Wu K, Liu Z, Lin C, et al. Placental leptin gene methylation and macrosomia during normal pregnancy. Mol Med Rep. 2014;9:1013–8.

    CAS  PubMed  Google Scholar 

  28. 28.

    Tobi EW, Lumey LH, Talens RP, Kremer D, Putter H, Stein AD, et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet. 2009;18:4046–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Schultz NS, Broholm C, Gillberg L, Mortensen B, Jorgensen SW, Schultz HS, et al. Impaired leptin gene expression and release in cultured preadipocytes isolated from individuals born with low birth weight. Diabetes. 2014;63:111–21.

    CAS  PubMed  Google Scholar 

  30. 30.

    Souren NY, Paulussen AD, Steyls A, Loos RJ, Stassen AP, Gielen M, et al. Common SNPs in LEP and LEPR associated with birth weight and type 2 diabetes-related metabolic risk factors in twins. Int J Obes. 2008;32:1233.

    CAS  Google Scholar 

  31. 31.

    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 Genetics. 2004;75:220–30.

    CAS  Google Scholar 

  32. 32.

    Hager J, Clement K, Francke S, Dina C, Raison J, Lahlou N, et al. A polymorphism in the 5′ untranslated region of the human ob gene is associated with low leptin levels. Int J Obes. 1998;22:200.

    CAS  Google Scholar 

  33. 33.

    Meirhaeghe A, Cottel D, Amouyel P, Dallongeville J. Lack of association between certain candidate gene polymorphisms and the metabolic syndrome. Mol Genetics Metab. 2005;86:293–9.

    CAS  Google Scholar 

  34. 34.

    Kilpeläinen TO, Carli JFM, Skowronski AA, Sun Q, Kriebel J, Feitosa MF, et al. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels. Nat Commun. 2016;7:10494.

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    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.

    PubMed  Google Scholar 

  36. 36.

    Nankervis A, McIntyre HD, Moses RG, Ross GP, Callaway LK. Testing for gestational diabetes mellitus in Australia. Diabetes Care. 2013;36:e64.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Tranquilli A, Dekker G, Magee L, Roberts J, Sibai B, Steyn W, et al. The classification, diagnosis and management of the hypertensive disorders of pregnancy: a revised statement from the ISSHP. Pregnancy Hypertens. 2014;4:97.

    CAS  PubMed  Google Scholar 

  38. 38.

    Schmelzle HR, Fusch C. Body fat in neonates and young infants: validation of skinfold thickness versus dual-energy X-ray absorptiometry. Am J Clin Nutr. 2002;76:1096–100.

    CAS  PubMed  Google Scholar 

  39. 39.

    de Onis M, Onyango AW, Van den Broeck J, Chumlea CW, Martorell R. Measurement and standardization protocols for anthropometry used in the construction of a new international growth reference. Food Nutr Bull. 2004;25(1_suppl1):S27–S36.

    PubMed  Google Scholar 

  40. 40.

    Cole TJ, Williams AF, Wright CM. Revised birth centiles for weight, length and head circumference in the UK-WHO growth charts. Ann Hum Biol. 2011;38:7–11.

    PubMed  Google Scholar 

  41. 41.

    WMGRS Group, Onis de, Growth MWHOChild. Standards based on length/height, weight and age. Acta Paediatr. 2006;95:76–85.

    Google Scholar 

  42. 42.

    Mansell T, Novakovic B, Meyer B, Rzehak P, Vuillermin P, Ponsonby AL, et al. The effects of maternal anxiety during pregnancy on IGF2/H19 methylation in cord blood. Transl Psychiatry. 2016;6:e765.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Lam D, Ancelin ML, Ritchie K, Saffery R, Ryan J. DNA methylation and genetic variation of the angiotensin converting enzyme (ACE) in depression. Psychoneuroendocrinology. 2018;88:1–8.

    CAS  PubMed  Google Scholar 

  44. 44.

    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. ClinTransl Immunol. 2015;4:e34.

    Google Scholar 

  45. 45.

    McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood AR, Teumer A, et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016;48:1279–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Turner S, Armstrong LL, Bradford Y, Carlson CS, Crawford DC, Crenshaw AT, et al. Quality Control Procedures for Genome-Wide Association Studies. Curr Protoc Hum Genetics. 2011;68:1.19.1–1.8.

    Google Scholar 

  47. 47.

    Martins MC, Trujillo J, Farias DR, GJNR Kac. Polymorphisms in the leptin (rs7799039) gene are associated with an increased risk of excessive gestational weight gain but not with leptin concentration during pregnancy. 2017;47:53–62.

  48. 48.

    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

  49. 49.

    Obermann-Borst SA, Eilers PH, Tobi EW, de Jong FH, Slagboom PE, Heijmans BT, et al. Duration of breastfeeding and gender are associated with methylation of the LEPTIN gene in very young children. Pediatr Res. 2013;74:344.

    CAS  PubMed  Google Scholar 

  50. 50.

    Muhlhausler BS, Duffield J, McMillen IC. Increased maternal nutrition stimulates peroxisome proliferator activated receptor-γ, adiponectin, and leptin messenger ribonucleic acid expression in adipose tissue before birth. Endocrinology. 2007;148:878–85.

    CAS  PubMed  Google Scholar 

  51. 51.

    Lesseur C, Armstrong DA, Murphy MA, Appleton AA, Koestler DC, Paquette AG, et al. Sex-specific associations between placental leptin promoter DNA methylation and infant neurobehavior. Psychoneuroendocrinology. 2014;40:1–9.

    CAS  PubMed  Google Scholar 

  52. 52.

    Krempler F, Breban D, Oberkofler H, Esterbauer H, Hell E, Paulweber B, et al. Leptin, peroxisome proliferator-activated receptor-γ, and CCAAT/enhancer binding protein-α mRNA expression in adipose tissue of humans and their relation to cardiovascular risk factors. Arterioscler Thromb Vas Biol. 2000;20:443–9.

    CAS  Google Scholar 

  53. 53.

    Ong KKL, Ahmed ML, Sherriff A, Woods KA, Watts A, Golding J, et al. Cord blood leptin is associated with size at birth and predicts infancy weight gain in humans. J Clin Endocrinol Metab. 1999;84:1145–8.

    CAS  PubMed  Google Scholar 

  54. 54.

    Sayeed SK, Zhao J, Sathyanarayana BK, Golla JP, Vinson C. C/EBPβ (CEBPB) protein binding to the C/EBP| CRE DNA 8-mer TTGC| GTCA is inhibited by 5hmC and enhanced by 5mC, 5fC, and 5caC in the CG dinucleotide. Biochim et Biophys Acta. 2015;1849:583–9.

  55. 55.

    Mise H, Sagawa N, Matsumoto T, Yura S, Nanno H, Itoh H, et al. Augmented placental production of leptin in preeclampsia: possible involvement of placental hypoxia. J Clinl Endocrinol Metab. 1998;83:3225–9.

    CAS  Google Scholar 

  56. 56.

    El Hajj N, Pliushch G, Schneider E, Dittrich M, Müller T, Korenkov M, et al. Metabolic programming of MEST DNA methylation by intrauterine exposure to gestational diabetes mellitus. Diabetes. 2013;62:1320–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Sherwood WB, Bion V, Lockett GA, Ziyab AH, Soto-Ramírez N, Mukherjee N, et al. Duration of breastfeeding is associated with leptin (LEP) DNA methylation profiles and BMI in 10-year-old children. Clin Epigenetics. 2019;11:1–10.

    CAS  Google Scholar 

  58. 58.

    Saenen ND, Vrijens K, Janssen BG, Roels HA, Neven KY, Vanden Berghe W, et al. Lower placental leptin promoter methylation in association with fine particulate matter air pollution during pregnancy and placental nitrosative stress at birth in the ENVIRONAGE Cohort. Environmental health perspectives. 2017;125:262–8.

    CAS  PubMed  Google Scholar 

  59. 59.

    Wang Y, Eliot MN, Kuchel GA, Schwartz J, Coull BA, Mittleman MA, et al. Long-term exposure to ambient air pollution and serum leptin in older adults: results from the MOBILIZE Boston study. J Occup Environ Med. 2014;56:e73.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Pereira-Fernandes A, Dirinck E, Dirtu AC, Malarvannan G, Covaci A, Van Gaal L, et al. Expression of obesity markers and persistent organic pollutants levels in adipose tissue of obese patients: reinforcing the obesogen hypothesis? PloS ONE. 2014;9:e84816.

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Kamstra JH, Hruba E, Blumberg B, Janesick A, Mandrup S, Hamers T, et al. Transcriptional and epigenetic mechanisms underlying enhanced in vitro adipocyte differentiation by the brominated flame retardant BDE-47. Environ Sci Technol. 2014;48:4110–9.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

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].

Author information

Affiliations

Authors

Consortia

Corresponding author

Correspondence to Richard Saffery.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Further reading

Search

Quick links