DNA methylation signatures at endoplasmic reticulum stress genes are associated with adiposity and insulin resistance

Omar Ramos-Lopez; Jose I Riezu-Boj; Fermin I Milagro; J Alfredo Martinez; MENA Project

doi:10.1016/j.ymgme.2017.11.011

DNA methylation signatures at endoplasmic reticulum stress genes are associated with adiposity and insulin resistance

Mol Genet Metab. 2018 Jan;123(1):50-58. doi: 10.1016/j.ymgme.2017.11.011. Epub 2017 Nov 28.

Authors

Omar Ramos-Lopez¹, Jose I Riezu-Boj², Fermin I Milagro³, J Alfredo Martinez⁴; MENA Project

Affiliations

¹ Department of Nutrition, Food Science and Physiology, Center for Nutrition Research, University of Navarra, Pamplona, Spain.
² Department of Nutrition, Food Science and Physiology, Center for Nutrition Research, University of Navarra, Pamplona, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
³ Department of Nutrition, Food Science and Physiology, Center for Nutrition Research, University of Navarra, Pamplona, Spain; Biomedical Research Centre Network in Physiopathology of Obesity and Nutrition (CIBERobn), Carlos III Institute, Madrid, Spain.
⁴ Department of Nutrition, Food Science and Physiology, Center for Nutrition Research, University of Navarra, Pamplona, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Biomedical Research Centre Network in Physiopathology of Obesity and Nutrition (CIBERobn), Carlos III Institute, Madrid, Spain; Madrid Institute of Advanced Studies (IMDEA Food), Madrid, Spain. Electronic address: jalfmtz@unav.es.

PMID: 29221916
DOI: 10.1016/j.ymgme.2017.11.011

Abstract

A sustained activation of the unfolded protein response and the subsequent endoplasmic reticulum (ER) stress has been involved in the onset and severity of several metabolic diseases. The aim of this study was to analyze the association of DNA methylation signatures at ER stress genes with adiposity traits and related metabolic disorders. An epigenomic analysis within the Methyl Epigenome Network Association (MENA) project was conducted in an adult population (n=474). DNA methylation status in peripheral white blood cells was analyzed by a microarray approach. KEGG database was used to the characterization and discrimination of genes involved in the "protein processing in endoplasmic reticulum pathway". Anthropometric measurements and plasma metabolic profiles were analyzed. A total of 15 CpG sites at genes participating in ER pathway were strongly correlated with BMI after adjusted linear regression analyses (p<0.0001). These included cg08188400 (MAP2K7), cg20541779 (CASP12), cg24776411 (EIF2AK1), cg14190817 (HSPA5), cg21376454 (ERN1), cg06666486 (EIF2AK1), cg03211481 (DNAJC1), cg18357645 (OS9), cg05801879 (MBTPS1), cg20964082 (ERO1LB), cg17300868 (NFE2L2), cg03384128 (EIF2AK4), cg02712587 (EIF2AK4), cg04972384 (SELS), cg02240686 (EIF2AK2). Noteworthy, most of them were implicated in ER stress (p=2.9E-09). However, only methylation levels at cg20964082 (ERO1LB), cg17300868 (NFE2L2), cg05801879 (MBTPS1), and cg03384128 (EIF2AK4) also correlated with total fat mass. Interestingly, significant associations between methylation patterns at cg20964082 (ERO1LB) and cg17300868 (NFE2L2) and insulin and HOMA-IR index were found, whereas cg05801879 (MBTPS1) and cg03384128 (EIF2AK4) were correlated with triglyceride levels. This study suggests associations of methylation signatures at ER stress genes with adiposity and insulin resistance, as revealed by discriminative pathway analyses.

Keywords: Endoplasmic reticulum; Epigenetics; Insulin resistance; Obesity; Triglycerides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adiposity / genetics*
DNA Methylation / genetics*
Endoplasmic Reticulum Chaperone BiP
Endoplasmic Reticulum Stress / genetics*
Epigenomics
Humans
Insulin Resistance / genetics*
Triglycerides / genetics

Substances

Endoplasmic Reticulum Chaperone BiP
HSPA5 protein, human
Triglycerides