Abstract
BackgroundBreastfeeding 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.MethodsIn 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.ResultsBoth total and exclusive breastfeeding duration were associated with DNAm at four LEP CpG sites at 10 years (P value < 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 < 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.ConclusionsBreastfeeding 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.
Highlights
The multiple health benefits of breastfeeding are well recognised, with the World Health Organization (WHO) recommending that infants should be exclusively breastfed up until 6 months and breastfed alongside complementary food until 2 years of age [1], though globally, a high proportion of infants are not breastfed according to international guidelines [2, 3].Infants who are not breastfed are at increased risk of all-cause and infection-related mortality [4]
The aim of this study was to replicate and extend the study by Obermann-Borst et al, in the Isle of Wight Birth Cohort (IOWBC) to test the association between breastfeeding and DNA methylation (DNAm) of cytosine-phosphate-guanines (CpGs) in Leptin gene (LEP) gene in peripheral blood at later ages (10 and 18 years) and further explore the association between breastfeeding duration and body mass index (BMI), where DNAm may act as a mediator
Stability of DNA methylation Intra-class correlation shows that 64.3% of the common cytosine-phosphate-guanine sites (CpGs) (9 out of 14) were fairly moderately stable (ICC between 0.05 to 0.75) over 8 years (Additional file 1: Table S2)
Summary
The multiple health benefits of breastfeeding are well recognised, with the World Health Organization (WHO) recommending that infants should be exclusively breastfed up until 6 months and breastfed alongside complementary food until 2 years of age [1], though globally, a high proportion of infants are not breastfed according to international guidelines [2, 3].Infants who are not breastfed are at increased risk of all-cause and infection-related mortality [4]. Long-term, adequate breastfeeding has been associated with a range of phenotypes including a lowered risk of type 2 diabetes [6], improved performance in intelligence tests [7], and reduced risk of childhood leukemia [8]. Several studies and meta-analyses have recently reported a significant association between breastfeeding duration and childhood obesity [6, 14, 15]. The WHO reports that breastfeeding appears to reduce the risk of being overweight and obese in childhood [16]. On the other hand, breastfeeding duration has been found to be associated with DNA methylation (DNAm) of the LEP gene. Epigenetic regulation of LEP may represent the mechanism underlying the protective effect of breastfeeding duration against obesity
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