Abstract P305: Obesity is Associated with Differentiated Methylation in Glucose Tolerance-related Genes in Adolescents
Background: Childhood obesity is related to increased cardiometabolic risk in adulthood. Insulin resistance is an established underlying mechanism between obesity and CVD risk. However, the role of epigenetic profiles in this mechanistic link is less investigated, especially in adolescents.
Hypothesis: We assessed the hypothesis that obesity is associated with differentiated methylation profiles in genes related to glucose tolerance and its downstream functions in adolescents.
Methods: We used data from a sample of 116 adolescents from the population-based Penn State Child Cohort follow-up exam (N=421). Among which, 22 were obese (BMI percentile ≥ 95) and 94 were normal weight (BMI percentile < 85). Peripheral leukocytes DNA was extracted and subject to enhanced reduced representation bisulfite sequencing. The high-throughput assay provided single nucleotide resolution of DNA methylation in CpG sites and surrounding regions. The R package methylKit was used in the post-processing and analysis. Bases with < 10x coverage were excluded in the assay, resulting in a total of 634,418 methylation sites with a minimum of 10 samples per group. Logistic regression was used in the differential methylation calculation. We decided a priori to choose the sites with ≥ 25% difference in methylation with a q value <0.01 for the enrichment analysis. We used Ingenuity Pathway Analysis (IPA) to perform gene-set enrichment analysis for downstream function and effects on the differentially methylated genes.
Results: The mean (SD) age of the study sample was 16.3 (2.2) years. The sample consisted of 52% male and 79% white. No significant difference was observed between obese and normal weight groups with respect to demographic characteristics. We identified a total of 2349 bases with statistically significant (q<0.01) differentiated methylation with a difference of 25% or more. IPA revealed 38 sites related to glucose tolerance function, and this function is significantly enriched (p=1.51E-4). Highlighting some individual genes, obese adolescents showed 26.4% higher methylation at a site on the insulin (INS) gene compared to normal weight adolescents, and a site on the gastric inhibitory polypeptide receptor (GIPR) gene had 47.3% differential methylation. Other major significantly differentially methylated glucose tolerance-related genes included interleukin 6 (IL6), and tumor necrosis factor (TNF), and low density lipoprotein receptor (LDLR) genes.
Conclusion: Obesity in adolescents is significantly associated with substantially differentiated methylation in glucose tolerance-related genes. It indicated that obesity is related to alternations in the epigenetic profiles related to impaired glucose tolerance, and potentially through which associated with elevated risk of its downstream diseases, such as diabetes and CVD.
Author Disclosures: F. He: None. A. Berg: None. Y. Imamura Kawasawa: None. A.C. Salzberg: None. E.O. Bixler: None. A.N. Vgontzas: None. D. Liao: None.
- © 2016 by American Heart Association, Inc.