Increased DNA methylation variability in type 1 diabetes across three immune effector cell types

Abstract

The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.

Twin-Studies on the Role of Non-Genetic Factors in T1D Pathogenesis

“…This study identified the methylation state of 88 CpG sites, showing a significant difference in the methylation between the affected and unaffected twins. They also found a marked difference in the DNA methylation of HLA, INS, IL-2RB and CD226 among T1D-discordant MZ twins [15]. Another study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types revealed a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and healthy unrelated individuals [14].…”

“…The global DNA hypomethylation within gene promoter regions may cause T1D, but single CpG sites alone may not contribute to the onset and pathogenesis of T1D [16]. Although twin-studies on type 1 diabetes suggest that the abnormal DNA methylation might act as a pivotal part in the etiology of T1D, hypermethylation in CpG sites of some genes can be also observed in affected discordant twins [15]. Similarly, it was reported that CD14+ and CD4+ cells of T1D quadruplets were hyper-and hypo-methylated [17].…”

“…A total of 83 monozygotic (MZ) twin pairs from European countries and the United States have been studied. Mihaela Stefan et al [15] analyzed 9 MZ twin pairs, in which 3 pairs discordant for T1D and 6 pairs concordant for the disease. This study identified the methylation state of 88 CpG sites, showing a significant difference in the methylation between the affected and unaffected twins.…”

“…The most likely environmental factor is congenital rubella, because children with congenital rubella syndrome eventually develop type 1 diabetes [25]. The common living environment factors, such as epigenetic [15], dietary habits [26], drugs [27], air pollutant [28], stress viral infections [29], gut microbiota [30], sunlight and Vitamin D [24], have been studied. The putative predisposing factors are viruses (enteroviruses and rotaviruses) and components of infant diet including gluten and milk.…”

Type 1 diabetes genome‐wide association studies: not to be lost in translation

“…13 In addition to genetic predisposition, environmental and epigenetic factors impact the disease susceptibility. 14, 15 …”