Epigenome-wide association study in peripheral white blood cells involving insulin resistance

Abstract

Insulin resistance (IR) is a hallmark of type 2 diabetes, metabolic syndrome and cardiometabolic risk. An epigenetic phenomena such as DNA methylation might be involved in the onset and development of systemic IR. The aim of this study was to explore the genetic DNA methylation levels in peripheral white blood cells with the objective of identifying epigenetic signatures associated with IR measured by the Homeostatic Model Assessment of IR (HOMA-IR) following an epigenome-wide association study approach. DNA methylation levels were assessed using Infinium Methylation Assay (Illumina), and were associated with HOMA-IR values of participants from the Methyl Epigenome Network Association (MENA) project, finding statistical associations for at least 798 CpGs. A stringent statistical analysis revealed that 478 of them showed a differential methylation pattern between individuals with HOMA-IR ≤ 3 and > 3. ROC curves of top four CpGs out of 478 allowed differentiating individuals between both groups (AUC≈0.88). This study demonstrated the association between DNA methylation in some specific CpGs and HOMA-IR values that will help to the understanding and in the development of new strategies for personalized approaches to predict and prevent IR-associated diseases.

PPARGC1A Gene Promoter Methylation as a Biomarker of Insulin Secretion and Sensitivity in Response to Glucose Challenges

“…We previously reported that the methylation levels of CpG sites in the PPARGC1A gene measured through Illumina 450K array did not reach significant association in relation to insulin sensitivity measured as HOMA-IR (from fasting blood samples) or CSi (from IVGTT) in the participants of the present study [47,48]. Using peripheral blood mononuclear cells as a source of DNA, another epigenome-wide study compared insulin-resistant versus insulin-sensitive non-diabetic women with obesity, classified according to hyperinsulinemic euglycemic clamps, without finding differences by PPARGC1A methylation status [41].…”

Mining the Selective Remodeling of DNA Methylation in Promoter Regions to Identify Robust Gene-Level Associations with Phenotype

“…As a result, 990 IR-associated genes were predicted by SIMPO-TSS1500 ( Table S9 ). On the other hand, starting from the same dataset, another study has identified a total of 478 CpGs based on the traditional method, covering 499 differential genes [34]. Because IR is a pathological condition in which cells fail to respond appropriately to insulin, and it is a hallmark of type 2 diabetes [34,38], we speculated that above IR-related differential genes are associated with diabetes.…”

“…On the other hand, starting from the same dataset, another study has identified a total of 478 CpGs based on the traditional method, covering 499 differential genes [34]. Because IR is a pathological condition in which cells fail to respond appropriately to insulin, and it is a hallmark of type 2 diabetes [34,38], we speculated that above IR-related differential genes are associated with diabetes. By querying the known diabetes-associated genes recorded in the SCG-Drug database, it was found that only 77 genes of the 499 genes (15.43%) identified by traditional methods were known as diabetes-associated genes.…”

“…This dataset uses Illumina HumanMethylation450 BeadChip’s GPL16304 platform and contains DNA methylation data of peripheral white blood cells collected from 74 HOMA-IR>3, and 258 HOMA-IR⩽3 individuals. Furthermore, based on this data, a rigorous statistical analysis revealed that 478 CpGs showed a differential methylation pattern between individuals with HOMA-IR ⩽ 3 and > 3 [34].…”

A randomized controlled trial for overweight and obesity in preschoolers: the More and Less Europe study - an intervention within the STOP project

“…Moreover, an increased methylation in the gene RXRA measured at birth has been associated with greater adiposity in later childhood [23]. Two other investigations identified a strong correlation between obesity and serum levels of micro RNA (miR)-122 and miR-519d [24] and found DNA methylation to be related to insulin resistance [25]. However, these findings need to be confirmed and further explored in young children.…”