Abstract MP55: DNA Methylation Mediates The Effects Of Obesity On Insulin Resistance In African American Youth And Young Adults

Abstract

Obesity and its related cardiovascular disease and type 2 diabetes have imposed huge burdens on public health worldwide. Insulin resistance is considered one of the key players in the development of obesity related comorbidities. However, the underlying mechanisms are still largely unknown. In this study, we aim to examine whether and to what extent peripheral blood DNA methylation can mediate obesity’s effect on insulin resistance using a genome-wide approach. Illumina 450k data were obtained for 456 black youth and young adults (226 obese cases vs. 230 lean controls) aged 14-34 years with fasting insulin levels available for 293 subjects and genome-wide gene expression data available for 92 subjects. As shown in figure 1, obesity and fasting insulin associated differentially methylated CpG sites were identified separately. Among the overlap of these 2 lists (n=69), 32 CpG sites mapping to 28 genes significantly mediated obesity’s effect on fasting insulin. Principal component analysis found that, in total, these 32 methylation sites explained up to 17.3% of the effect of obesity on insulin. Among these mediators, the top CpG site is located in the promoter region of the LIPA (lipase A) gene, and this single CpG site explained 8.4% of the effect of obesity on insulin. Consistent with the higher methylation levels observed in the obese group, LIPA expression was decreased in the obese group (p=0.038). A significant negative partial correlation was also found between LIPA methylation levels and its expression levels (p=0.01, r=-0.26). Genetic variants in LIPA have been suggested to contribute to the interindividual variability in metabolic traits observed among obese individuals. In summary, we observed that peripheral blood DNA methylation mediates obesity’s effect on insulin resistance in African American youth and young adults, explaining up to 17% of the effect.