DNA methylation and gene expression analysis in adipose tissue to identify new loci associated with T2D development in obesity

BACKGROUND: Obesity-related excess adipose storage can lead to adipose dysfunction, insulin resistance, and type 2 diabetes (T2D). Genetic variation alone does not explain T2D susceptibility in obesity; epigenetic mechanisms such as DNA methylation may be involved. We aimed to identify DNA methylation and gene expression changes in visceral adipose tissue (VAT) underlying T2D susceptibility in patients with obesity. METHODS: VAT biopsies from 19 women with obesity without (OND = 9) or with T2D (OD = 10) were profiled by Illumina EPIC (850K) methylation arrays and Affymetrix Clariom S expression arrays. Differentially methylated CpGs (DMCs; FDR < 0.05), differentially methylated regions (DMRs; p < 0.05), and differentially expressed genes (DEGs; p < 0.05 with logFC > 0.5) were identified. Overlap between methylation and expression changes and impact of methylation on expression were assessed with bootstrap Pearson correlation. Associations of methylation with fasting glucose and HbA1c were evaluated. RESULTS: We identified 11,120 DMCs and 96 DMRs across all chromosomes, with the greatest density at the MHC locus. Alterations involved newly and previously T2D-related genes, supported by validation and extended multi-ethnic analyses. Among 252 DEGs, 68 genes harbored 88 DMCs; 24 genes showed significant methylation–expression relationships. Of these, 16 (including ATP11A, LPL, and EHD2) also correlated with fasting glucose and HbA1c. CONCLUSIONS: Novel candidate genes related to T2D pathogenesis in obesity exhibit perturbations in VAT DNA methylation and expression. Methylation profiles discriminated OND from OD individuals, highlighting DNA methylation as a potential biomarker.

Paulina Baca, Francisco Barajas-Olmos, Elaheh Mirzaeicheshmeh, Carlos Zerrweck, Lizbeth Guilbert, Ernesto Carlos Sánchez, Marlen Flores-Huacuja, Rafael Villafán, Angélica Martínez-Hernández, Humberto García-Ortiz, Cecilia Contreras-Cubas, Federico Centeno-Cruz, Lorena Orozco