243-OR: Integrative Multiomics Analysis of Glucometabolic Traits, Adipose Tissue DNA Methylation, and Gene Expression Identifies Epigenetic Regulatory Mechanisms of Insulin Resistance and Obesity in African Americans

Decline in insulin sensitivity due to dysfunction of adipose tissue (AT) is one of the earliest pathogenic events in type 2 diabetes. We hypothesize that differential DNA methylation (DNAm) in regulatory regions of a subset of genes controls insulin sensitivity and obesity by modulating transcript expression in AT. Integrating reduced representation bisulfite sequencing-derived AT DNAm profiles for 1,054,719 CpG sites and 200,800 CpG regions with AT transcript profile data in 230 African Americans, we performed cis-expression quantitative trait methylation (cis-eQTM) analysis focused on 6,774 glucometabolic trait-associated transcripts to identify local epigenetic regulatory loci for these transcripts. We identified significantly associated CpG regions for 140 transcripts (FDR-P<0.1). The strongest eQTM locus was observed for the proopiomelanocortin (POMC; ρ= -0.632, P = 4.70X10^-27) gene at the chr2:25,384,001-25,385,000 region covering a CpG island in the gene. Epigenome-wide association studies (EWAS) further examined the association of DNAm levels of CpG sites/regions with insulin sensitivity (Matsuda index and S_I) and BMI. EWAS identified 520, 154, and 482 CpG regions associated (FDR-P <0.1) with Matsuda index, S_I and BMI, respectively. We jointly analyzed the EWAS, transcript level to trait association, and eQTM data and identified significant eQTM loci for 26, 15 and 25 genes that were also associated with Matsuda index, S_I and BMI, respectively in EWAS. These associated genes include fructose-2,6-biphosphatase 3 (PFKFB3), integrin alpha M (ITGAM), integrin alpha X (ITGAX), and POMC.

In summary, applying an integrative multi-omics approach, our study provides evidence for DNAm-mediated regulation of gene expression at both previously identified and novel loci for many key AT transcripts influencing insulin resistance and obesity.