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.

Genome-wide DNA methylation variability in adolescent monozygotic twins followed since birth

“…26 Moreover, both Gordon and colleagues 17 and Saffery and colleagues 27 found that the most discordantly methylated genes from cord blood mononuclear cells (CBMCs) and human umbilical vascular endothelial cells (HUVECs) were those shown to be involved in responding to the environment. Additionally, studies have found within-pair DNA methylation discordance in association with autism, 28,29 bipolar disorder, 30 risk taking behavior, 31 Alzheimer disease, 32 intestinal disease, 23 diabetes, [33][34][35] and even birth weight. 25 See Table S1 for a summary of epigenetic findings in MZ twins.…”

Enterovirus Infection and Type 1 Diabetes: Closing in on a Link?

“…(1). Due to the divergence seen in monozygotic twin cohorts, we know that both genetic and environmental factors must contribute to the development of human type 1 diabetes (T1D) (2,3). For many decades, we have searched for environmental triggers, but it has remained difficult to define the key players.…”

Az 1-es típusú diabetes genetikája: jelen és jövő

“…Általában a gének promóter régiójában találhatók azok a citozin-guanin dinukleotidok (úgynevezett CpG-szigetek), ahol a DNS-metiltranszferázok egy metilcsoport kovalens kötését katalizálva transzkripcionális gén-csendesítést eredményeznek [2]. Más autoimmun betegségekhez hasonlóan 1-es típusú diabetesben is kimutatták, hogy bizonyos gének (például HLA, INS, IL-2RA, IL-2RB, CD226) promóter régiójában a csökkent DNS-metiltranszferáz-aktivitás miatt a CpGmetiláció hibás, ami génexpressziós diszregulációt, kromoszomális instabilitást és fokozott autoimmun hajlamot eredményezhet [34][35][36][37]. A metilációs profil vizsgálatának korai predikciós és prognosztikai haszna lehet, hiszen diabeteses egereknél a metilációspecifikus kvantitatív polimeráz láncreakciót sikeresen alkalmazták a keringő béta-sejt-DNS perifériás vérből történő kimutatására, a béta-sejt-pusztulás monitorozására és a diabetes kezdetének megjóslására.…”