Journal
DIABETES
Volume 69, Issue 12, Pages 2779-2793Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db20-0117
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Funding
- American Diabetes Association Innovative Clinical or Translational Science Research Award [1-18-ICTS-113]
- National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-090111, R01-DK-118243]
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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 (AAs) from the African American Genetics of Metabolism and Expression cohort, we performed cis-expression quantitative trait methylation (cis-eQTM) analysis to identify epigenetic regulatory loci for glucometabolic trait-associated transcripts. We identified significantly associated cytosine-guanine dinucleotide regions for 82 transcripts (false discovery rate [FDR]-P < 0.05). The strongest eQTM locus was observed for the proopiomelanocortin (POMC; rho = -0.632, P = 4.70 x 10(-27)) gene. Epigenome-wide association studies (EWAS) further identified 155, 46, and 168 cytosine-guanine dinucleotide regions associated (FDR-P < 0.05) with the Matsuda index, S-I, 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-I, and/or BMI in EWAS. These associated genes include FERMT3, ITGAM, ITGAX, and POMC. In summary, applying an integrative multiomics 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.
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