Childhood obesity is associated with various diseases throughout the lifespan, including hypertension and insulin resistance. Multiple "omic" factors related to obesity risk have been identified, such as genomic, microbiome, and epigenomic factors.
Previous studies have indicated that 40-80% of BMI variation can be explained by genetic factors. However, the cumulative effect of the single nucleotide polymorphisms (SNPs) discovered so far does not account for all genetic variation. Specifically, early genome-wide association studies (GWAS) could only explain about 3% of BMI variation. Although meta-analyses have raised this percentage to over 20%, they still cannot explain the observed heritability of obesity, which is close to 50%. Despite this gap, many studies continue to extensively develop polygenic risk scores (PRS) and incorporate variations from GWAS to assess individual disease risk.
In addition to genetic factors, epigenetic modifications can provide important insights into an individual's obesity risk, as they can be inherited when present in the germline and can be modified by environmental factors. The most common epigenetic modification of DNA is cytosine methylation at CpG sites. When methylation occurs in regulatory regions, it plays a role in suppressing gene expression; when it occurs within gene bodies, it is associated with active gene transcription. Similar to polygenic risk scores (PRS) constructed using SNP data, methylation risk score (MRS) models have been developed. MRS is a linear combination of the methylation status of multiple CpG sites and may be useful in clinical settings, as these epigenetic markers can be influenced by environmental conditions, thus enabling the monitoring of disease risk over time.
In the context of childhood obesity, some studies have shown differences in peripheral blood methylation patterns between overweight and non-overweight children. Other studies have identified certain CpG sites whose methylation status in cord blood is associated with obesity in children aged 3 to 7 and under 18 years old. The methylation patterns in children's cord blood reflect influences from maternal methylation patterns and environmental factors affecting pregnancy. Moreover, MRS has been found to be associated with BMI in both adults and children. However, the MRS used in previous studies on children were derived from epigenome-wide association studies (EWAS) on adult BMI. Therefore, it remains unclear whether there are specific gene methylation patterns present at birth that are related to early childhood growth.
The authors conducted a genome-wide DNA methylation analysis using the Illumina Infinium MethylationEpic chip and incorporated information on children's and maternal health and various environmental factors into the regression analysis. Among the many genes that best predicted infant weight outcomes, 23 relevant genes were identified in cord blood and 10 in the placenta. Notably, in cord blood, the methylation status of three genes (PLIN4, UBE2F, and PPP1R16B) was associated with the three weight indicators studied. Additionally, based on the NSIGHT and SIBSIGHT studies on children's health and growth, there is clinical evidence for early interventions in preventing sibling childhood obesity. In the SIBSIGHT study, the authors examined the methylation of the aforementioned genes in cord blood and placental samples from 48 children and found associations with early childhood growth. Ultimately, the authors developed a methylation risk score (MRS) model that can identify children most likely to develop childhood obesity, enabling early preventive interventions.
Reference:
Journal of Developmental Origins of Health and Disease , Volume 15 , 2024 , e7