Epigenome-wide association in adipose tissue from the METSIM cohort

Abstract

Most epigenome-wide association studies to date have been conducted in blood. However, metabolic syndrome is mediated by a dysregulation of adiposity and therefore it is critical to study adipose tissue in order to understand the effects of this syndrome on epigenomes. Therefore, to determine if natural variation in DNA methylation was associated with metabolic syndrome traits, we profiled global methylation levels in subcutaneous abdominal adipose tissue. We measured association with 32 clinical traits related to diabetes and obesity in 201 people from the Metabolic Syndrome In Men cohort. We performed epigenome-wide association studies between DNA methylation levels and traits, and identified significant associations for 13 clinical traits in 21 loci. We prioritized candidate genes using eQTL, and identified 18 high confidence candidate genes, including known and novel genes associated with diabetes and obesity traits. We also carried out an analysis to identify which cell types may be mediating the associations, and concluded that most of the loci we identified were specific to adipocytes. We determined whether the abundance of cell types varies with metabolic traits, and found that macrophages increased in abundance with the severity of metabolic syndrome traits. Finally, we developed a DNA methylation based biomarker to assess type II diabetes risk in adipose tissue. In conclusion, our results demonstrate that profiling DNA methylation in adipose tissue is a powerful tool for understanding the molecular effects of metabolic syndrome on adipose tissue, and can be used in conjunction with traditional genetic analyses to further characterize this disorder.. CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/223495 doi: bioRxiv preprint first posted online 3 INTRODUCTIONMetabolic syndrome traits such as obesity, dyslipidemia, insulin resistance, and hypertension underlie the common forms of atherosclerosis, type 2 diabetes (T2D) and heart failure, which together account for the majority of deaths in Western populations. Metabolic syndrome affects 44% of adults over the age of 50 in the US, and people affected with metabolic syndrome have higher risk of heart attacks, diabetes and stroke (1). Numerous studies have investigated the genetic basis of metabolic syndrome traits such as diabetes (2), and accumulating evidence suggests that epigenetics is associated with these phenotypes (3, 4).Methylation of DNA cytosine bases is evolutionarily conserved and plays important roles in development, cell differentiation, imprinting, X-chromosome inactivation, and regulation of gene expression. Aberrant DNA methylation in mammals is associated with both rare and complex traits including cancer, aging (5), and imprinting disorders such as Prader-Willi syndrome. Recent studies have demonstrated that much like ...

The integrative biology of type 2 diabetes

“…Some gene loci recently identified to associate with insulin resistance are associated with insulin resistance at a given level of adiposity and modulate insulin sensitivity via adipocyte differentiation 113 , supporting the concept that limited WAT storage capacity rather than overall fat mass is the main contributor to insulin resistance and associated diseases. Epigenetic adipose tissue modifications may further influence these interactions 114 .…”

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