DNA methylation mediates development of HbA1c-associated complications in type 1 diabetes.
DNA methylation mediates development of HbA1c-associated complications in type 1 diabetes.
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DNA甲基化介导了1型糖尿病中HBA1C相关并发症的发展。
DOI：
10.1038/s42255-020-0231-8
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发表时间：
2020-08
影响因子：
20.8
通讯作者：
Natarajan R
中科院分区：
文献类型：
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作者：
Chen Z;Miao F;Braffett BH;Lachin JM;Zhang L;Wu X;Roshandel D;Carless M;Li XA;Tompkins JD;Kaddis JS;Riggs AD;Paterson AD;DCCT/EDIC Study Group;Natarajan R
在糖尿病控制和并发症试验（DCCT）和糖尿病干预和并发症流行病学（EDIC）随访研究中观察到代谢记忆，早期血糖控制对预防/延迟糖尿病并发症发展的持续益处，但机制仍不清楚。在这里，我们通过检查表观遗传DNA甲基化（DNAme）与先前血糖史的相关性，以及与499名随机选择的DCCT/EDIC参与者的血液DNA中18年内并发症的发生的相关性，显示了表观遗传DNA甲基化（DNAme）在代谢记忆中的参与。我们在186个CpG（FDR<15%，包括FDR<5%的43个）上证明了DCCT关闭附近的DNAme与DCCT期间的平均HbA 1c（平均DCCT-HbA 1c）之间的关联，其中许多位于并发症相关基因中。生物学功能探索研究表明，这些CpG富含C/EBP转录因子结合位点，以及血细胞和造血干细胞中的增强子/转录区，以及骨髓细胞中的开放染色质状态。中介分析显示，值得注意的是，几种CpG组合解释了平均DCCT-HbA 1c与EDIC期间并发症发生风险的68-97%的相关性。总之，关键CpG上的DNAme似乎通过修饰骨髓和其他细胞上的增强子活性来介导高血糖症和代谢记忆并发症之间的关联。
Metabolic memory, the persistent benefits of early glycemic control on preventing/delaying diabetic complications development, is observed in the Diabetes Control and Complications Trial (DCCT) and in the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study, but mechanisms remain unclear. Here, we show the involvement of epigenetic DNA methylation (DNAme) in metabolic memory by examining its associations with preceding glycemic history, and with subsequent development of complications over an 18-year period in blood DNAs of 499 randomly-selected DCCT/EDIC participants with type 1 diabetes. We demonstrate the associations between DNAme near DCCT-closeout and mean HbA1c during DCCT (mean-DCCT-HbA1c) at 186 CpGs (FDR<15%, including 43 at FDR<5%), many of which are located in complications-related genes. Biological function exploration studies reveal these CpGs are enriched in C/EBP transcription factor binding sites, as well as enhancer/transcription regions in blood cells and hematopoietic stem cells, and open chromatin states in myeloid cells. Mediation analyses show that, remarkably, several CpGs in combination explain 68–97% of the association of mean-DCCT-HbA1c with the risk of complications development during EDIC. In summary, DNAme at key CpGs appears to mediate the association between hyperglycemia and complications in metabolic memory, through modifying enhancer activity at myeloid and other cells.