Childhood DNA methylation as a marker of early life rapid weight gain and subsequent overweight

Abstract

Background High early postnatal weight gain has been associated with childhood adiposity; however, the mechanism remains unknown. DNA methylation is a hypothesised mechanism linking early life exposures and subsequent disease. However, epigenetic changes associated with high early weight gain have not previously been investigated. Our aim was to investigate the associations between early weight gain, peripheral blood DNA methylation, and subsequent overweight/obese. Data from the UK Avon Longitudinal study of Parents and Children (ALSPAC) cohort were used to estimate associations between early postnatal weight gain and epigenome-wide DNA CpG site methylation (Illumina 450 K Methylation Beadchip) in blood in childhood (n = 125) and late adolescence (n = 96). High weight gain in the first year (a change in weight z‐scores > 0.67), both unconditional (rapid weight gain) and conditional on birthweight (rapid thrive), was related to individual CpG site methylation and across regions using the meffil pipeline, with and without adjustment for cell type proportions, and with 5% false discovery rate correction. Variation in methylation at high weight gain-associated CpG sites was then examined with regard to body composition measures in childhood and adolescence. Replication of the differentially methylated CpG sites was sought using whole-blood DNA samples from 104 children from the UK Southampton Women’s Survey. Results Rapid infant weight gain was associated with small (+ 1% change) increases in childhood methylation (age 7) for two distinct CpG sites (cg01379158 (NT5M) and cg11531579 (CHFR)). Childhood methylation at one of these CpGs (cg11531579) was also higher in those who experienced rapid weight gain and were subsequently overweight/obese in adolescence (age 17). Rapid weight gain was not associated with differential DNA methylation in adolescence. Childhood methylation at the cg11531579 site was also suggestively associated with rapid weight gain in the replication cohort. Conclusions This study identified associations between rapid weight gain in infancy and small increases in childhood methylation at two CpG sites, one of which was replicated and was also associated with subsequent overweight/obese. It will be important to determine whether loci are markers of early rapid weight gain across different, larger populations. The mechanistic relevance of these differentially methylated sites requires further investigation.

Insulin Resistance and Cancer: In Search for a Causal Link

“…Among the numerous differential DNA methylation patterns associated with obesity in epigenome-wide association studies [ 193 , 196 ], the up-regulation of SOCS3 following hypomethylation has been recently reported to increase the risk of IR and diabetes [ 197 ]. Moreover, differentially methylated CpG sites during the first year of life have been found to be associated with early weight gain and later childhood obesity, thus suggesting that early-life epigenetic changes may predict an individual’s future risk of obesity and obesity-related comorbidities [ 198 ]. However, the significance of DNA methylation in the development of obesity and the risk to develop type 2 diabetes has not always been shown [ 193 ], and there is some suggestion that variation in DNA methylation can occur in response to changes in BMI [ 198 ].…”

Emerging roles of epigenetic regulation in obesity and metabolic disease

“…Furthermore, because different fat depots, including visceral WAT, subcutaneous WAT, and brown adipose tissue, are equipped with distinct DNA methylation landscapes, investigating whether DNA methylation mediates fat depot-specific function by maintaining distinct chromosome loops in different fat depots will be interesting. In addition, nutritional status during prenatal or early life has been suggested to contribute to an aberrant DNA methylation landscape, which profoundly affects the risks of metabolic disorders later in life ( 64 , 65 , 66 ). Thus, the role of DNA methylation in the regulation of 3D chromosome architecture may provide new insights into understanding the mechanistic connection of dysregulated WAT-specific DNA methylome in early life with metabolic pathologies observed in later life ( 67 ).…”

Genetics, epigenetics and transgenerational transmission of obesity in children

“…Indeed, a recent EWAS by Robinson et al, based on the UK Avon Longitudinal study of Parents and Children (ALSPAC) cohort was able to identify for the first time the association between a differential DNA methylation profiles of blood samples in children with early life rapid weight gain. The candidate gene analysis on ALSPAC and in the replication cohort found a positive association between rapid growth gain and DNA methylation at the locus near the checkpoint with forkhead and ring finger domains (CHFR) (cg11531579) gene encoding for E3 ubiquitin- protein ligase, thus increasing the risk of subsequent pediatric overweight/obesity ( 98 ).…”