Medical Genomics, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
Nat Commun. 2016 Nov 29;7:13555. doi: 10.1038/ncomms13555.
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.
过去十年中，1 型糖尿病（T1D）的发病率显著增加，表明非遗传因素（如表观遗传机制）在疾病发展中起作用。在这里，我们在三个免疫效应细胞类型中对 52 对 T1D 单卵双胞胎中的 406,365 个 CpG 进行了全基因组关联研究。与健康的同卵双胞胎相比，与健康的无关个体相比，我们观察到 T1D 双胞胎中差异可变 CpG 位置（DVPs）显著富集。这些与 T1D 相关的 DVPs 被发现具有时间稳定性，并在基因调控元件中富集。与特定于细胞类型的基因调控回路的整合突出了涉及免疫细胞代谢和细胞周期的途径，包括 mTOR 信号传导。来自进展为显性 T1D 的新生儿脐带血的证据表明，这些 DVPs 可能在出生后出现。我们的研究结果基于 772 个甲基组，暗示了可能导致 T1D 发病机制的表观遗传变化。
