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An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis.

TitleAn integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis.
Publication TypeJournal Article
Year of Publication2019
AuthorsLiu J, Carnero-Montoro E, van Dongen J, Lent S, Nedeljkovic I, Ligthart S, Tsai P-C, Martin TC, Mandaviya PR, Jansen R, Peters MJ, Duijts L, Jaddoe VWV, Tiemeier H, Felix JF, Willemsen G, de Geus EJC, Chu AY, Levy D, Hwang S-J, Bressler J, Gondalia R, Salfati EL, Herder C, Hidalgo BA, Tanaka T, Moore AZenobia, Lemaitre RN, Jhun MA, Smith JA, Sotoodehnia N, Bandinelli S, Ferrucci L, Arnett DK, Grallert H, Assimes TL, Hou L, Baccarelli A, Whitsel EA, van Dijk KWillems, Amin N, Uitterlinden AG, Sijbrands EJG, Franco OH, Dehghan A, Spector TD, Dupuis J, Hivert M-F, Rotter JI, Meigs JB, Pankow JS, van Meurs JBJ, Isaacs A, Boomsma DI, Bell JT, Demirkan A
Secondary Authorsvan Duijn CM
JournalNat Commun
Date Published2019 06 13
KeywordsAdult, Aged, Aged, 80 and over, Computer Simulation, CpG Islands, Diabetes Mellitus, Type 2, DNA Methylation, Epigenesis, Genetic, Epigenomics, Female, Gene Expression Profiling, Gene Expression Regulation, Genome-Wide Association Study, Glucose, Homeostasis, Humans, Insulin, Male, Metabolic Networks and Pathways, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Young Adult

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.

Alternate JournalNat Commun
PubMed ID31197173
PubMed Central IDPMC6565679
Grant ListK24 DK080140 / DK / NIDDK NIH HHS / United States
U01 AG061359 / AG / NIA NIH HHS / United States
T32 HL098049 / HL / NHLBI NIH HHS / United States
K01 HL130609 / HL / NHLBI NIH HHS / United States
VIDI 016.136.361 / / Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research) / International