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

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