An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis
An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis
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DOI：
10.1038/s41467-019-10487-4
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发表时间：
2019-06-13
影响因子：
16.6
通讯作者：
van Duijn, Cornelia M.
中科院分区：
文献类型：
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作者：
Liu, Jun;Carnero-Montoro, Elena;van Duijn, Cornelia M.
尽管已有关于2型糖尿病（T2D）和肥胖症中差异DNA甲基化的报道，但我们对其功能相关性的理解仍然有限。在这里，我们通过对4808名处于发现阶段的非糖尿病欧洲人和11，750名处于复制阶段的人进行的基于血液的表观基因组全关联研究，显示了T2D病理学早期阶段差异甲基化的影响。我们鉴定了与空腹胰岛素相关的LETM 1、RBM20、IRS 2、MAN 2A2和1q25.3区域中的CpG，以及与空腹血糖相关的FCRL 6、SLAMF 1、APOBEC 3H和15q26.1区域中的CpG。计算机交叉组学分析突出了差异甲基化在适应性免疫系统和葡萄糖稳态之间的串扰中的作用。差异甲基化至少解释了肥胖与胰岛素之间16.9%的相关性。我们的研究揭示了T2D早期发病机制中驱动差异甲基化和基因表达的遗传变异之间的生物学相互作用。
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.