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Background  Breastfeeding is protective against many long-term diseases, yet the mechanisms involved are unknown. Leptin gene ( LEP ) is reported to be associated with body mass index (BMI). On the other hand, breastfeeding duration has been found to be associated with DNA methylation (DNAm) of the  LEP  gene. Therefore, epigenetic regulation of  LEP  may represent the mechanism underlying the protective effect of breastfeeding duration against obesity.    Methods  In the Isle of Wight Birth Cohort, peripheral blood DNAm at 23 cytosine-phosphate-guanine sites (CpGs) in the  LEP  locus in 10-year-old ( n  = 297) samples and 16 CpGs in 18-year-old ( n  = 305) samples, were generated using the Illumina Infinium MethylationEPIC and HumanMethylation450 Beadchips respectively and tested for association with breastfeeding duration (total and exclusive) using linear regression. To explore the association between breastfeeding durations and genome-wide DNAm, epigenome-wide association studies (EWASs) and differential methylation region (DMR) analyses were performed. BMI trajectories spanning the first 18 years of life were used as the outcome to test the association with breastfeeding duration (exposure) using multi-nominal logistic regression. Mediation analysis was performed for significant CpG sites.    Results  Both total and exclusive breastfeeding duration were associated with DNAm at four  LEP  CpG sites at 10 years ( P  value &lt; 0.05), and not at 18 years. Though no association was observed between breastfeeding duration and genome-wide DNAm, DMR analyses identified five significant differentially methylated regions (Sidak adjusted  P  value &lt; 0.05). Breastfeeding duration was also associated with the early transient overweight trajectory. Furthermore, DNAm of  LEP  was associated with this trajectory at one CpG site and early persistent obesity at another, though mediation analysis was not significant.    Conclusions  Breastfeeding duration is associated with  LEP  methylation at age 10 years and BMI trajectory.  LEP  DNAm is also significantly associated with BMI trajectories throughout childhood, though sample sizes were small. However, mediation analysis did not demonstrate that DNAm of  LEP  explained the protective effect of breastfeeding against childhood obesity.    Electronic supplementary material  The online version of this article (10.1186/s13148-019-0727-9) contains supplementary material, which is available to authorized users.

Duration of breastfeeding is associated with leptin (LEP) DNA methylation profiles and BMI in 10-year-old children