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) controls insulin sensitivity and obesity by modulating
transcript expression in AT. Integrating AT DNAm profiles with transcript
profile data measured in a cohort of 230 African Americans from AAGMEx cohort, we
performed <i>cis</i>-expression quantitative trait methylation (<i>cis</i>-eQTM)
analysis to identify epigenetic regulatory loci for glucometabolic
trait-associated transcripts. We identified significantly associated CpG-regions
for 82 transcripts (FDR-P<0.05). The strongest eQTM locus was observed for
the proopiomelanocortin (<i>POMC</i>; r= -0.632, P= 4.70X10<sup>-27</sup>)
gene. Epigenome-wide association studies (EWAS) further identified 155, 46, and
168 CpG regions associated (FDR-P <0.05) with Matsuda index, S<sub>I</sub>
and BMI, respectively. Intersection of EWAS, transcript level to trait
association, and eQTM results, followed by causal inference test identified
significant eQTM loci for 23 genes that were also associated with Matsuda
index, S<sub>I </sub>and/or BMI in EWAS. These associated genes include <i>FERMT3</i>, <i>ITGAM</i>, <i>ITGAX</i>, and <i>POMC</i>.
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.
Integrative analysis of glucometabolic traits, adipose tissue DNA methylation and gene expression identifies epigenetic regulatory mechanisms of insulin resistance and obesity in African Americans
