title: DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology.
abstract: Type 1 diabetes (T1D) shows ∼40% concordance rate in monozygotic twins (MZ) suggesting a role for environmental factors and/or epigenetic modifications in the etiology of the disease. The aim of our study was to dissect the contribution of epigenetic factors, particularly, DNA methylation (DNAm), to the incomplete penetrance of T1D. We performed DNAm profiling in lymphocyte cell lines from 3 monozygotic (MZ) twin pairs discordant for T1D and 6 MZ twin pairs concordant for the disease using HumanMethylation27 BeadChip. This assay assesses the methylation state of 27,578 CpG sites, mostly located within proximal promoter regions. We identified 88 CpG sites displaying significant methylation changes in all T1D-discordant MZ twin pairs. Functional annotation of the genes with distinct CpG methylation profiles in T1D samples showed differential DNAm of immune response and defense response pathways between affected and unaffected twins. Integration of DNAm data with GWAS data mapped several known T1D associated genes, HLA, INS, IL-2RB, CD226, which showed significant differences in DNAm between affected and unaffected of twins. Our findings suggest that abnormalities of DNA methylation patterns, known to regulate gene transcription, may be involved in the pathogenesis of T1D.
authors.affiliation: Division of Endocrinology, Mount Sinai School of Medicine, New York, NY 10029, USA; James J. Peters Veterans Administration Medical Center, Bronx, NY 10468, USA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Stefan
authors.affiliation: Department of Medicine Bioinformatics Core, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Division of Endocrinology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Erlinda
authors.initials: E
authors.lastname: Concepcion
authors.affiliation: Department of Medicine Bioinformatics Core, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Zhengzi
authors.initials: Z
authors.lastname: Yi
authors.affiliation: Division of Endocrinology, Mount Sinai School of Medicine, New York, NY 10029, USA; James J. Peters Veterans Administration Medical Center, Bronx, NY 10468, USA. Electronic address: Yaron.Tomer@mssm.edu.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Tomer
mesh_terms: D000293:Adolescent; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands; D019175:DNA Methylation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007223:Infant; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics / Q000276:immunology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D014430:Twins, Monozygotic; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D006680:HLA Antigens; D053646:Interleukin-2 Receptor beta Subunit
keywords: DNA methylation; Monozygotic twins; Transcriptional regulation; Type 1 diabetes