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Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.

Original publication

DOI

10.1038/s41467-019-10487-4

Type

Journal article

Journal

Nature communications

Publication Date

13/06/2019

Volume

10

Addresses

Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015GD, The Netherlands. jun.liu@ndph.ox.ac.uk.

Keywords

Humans, Diabetes Mellitus, Type 2, Obesity, Insulin, Glucose, Gene Expression Profiling, DNA Methylation, Gene Expression Regulation, Epigenesis, Genetic, CpG Islands, Homeostasis, Polymorphism, Single Nucleotide, Computer Simulation, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Metabolic Networks and Pathways, Genome-Wide Association Study, Young Adult, Epigenomics