Alterations of 5-hydroxymethylcytosines in circulating cell-free DNA reflect retinopathy in type 2 diabetes
Alterations of 5-hydroxymethylcytosines in circulating cell-free DNA reflect retinopathy in type 2 diabetes
复制标题
DOI：
10.1016/j.ygeno.2020.11.014
复制
发表时间：
2021-01-01
期刊：
影响因子：
4.4
通讯作者：
Duan, Shiwei
中科院分区：
文献类型：
--
作者：
Han, Liyuan;Chen, Chang;Duan, Shiwei
糖尿病视网膜病变（DR）是2型糖尿病（T2 DM）患者常见的微血管并发症，可导致严重的视力损害和失明。DR的早期检测将扩大潜在治疗选择的范围，并能够更好地控制疾病进展。表观遗传失调与T2 DM患者微血管并发症的发病机制有关。我们试图探索5-羟甲基胞嘧啶（5 hmC）在循环游离DNA（cfDNA）中对DR的诊断价值，利用高度敏感的技术，5 hmC-Seal。使用5 hmC-Seal获得来自35名诊断为DR的患者和35名年龄、性别、糖尿病持续时间匹配的T2 DM对照的cfDNA样本中的全基因组5 hmC谱，随后进行病例对照分析和外部验证。来自DR患者的cfDNA中5 hmC的基因组分布反映了潜在的基因调控相关性，显示出与组蛋白修饰标记的共定位，用于活性表达（例如，H3K4me1）。一个三基因签名在多变量logistic回归模型上使用弹性网络正则化检测与DR相关的MESP 1、LY 6 G6 D、LINC 01556，显示出区分DR患者与T2 DM对照的高准确性（AUC [曲线下面积] = 91.4%; 95%CI [置信区间]，84.3- 98.5%），实现了88.6%的灵敏度和91.4%的特异性。在外部测试集中，5 hmC模型检测到6名DR患者中的5名，并预测8名非DR患者中的7名患有其他微血管并发症。来自DR患者的循环cfDNA含有可用于DR检测的5 hmC信息。作为一种新型的非侵入性方法，5 hmC-Seal有望成为T2 DM患者护理和监测工具的组成部分。
Diabetic retinopathy (DR) is a common microvascular complication that may cause severe visual impairment and blindness in patients with type 2 diabetes mellitus (T2DM). Early detection of DR will expand the range of potential treatment options and enable better control of disease progression. Epigenetic dysregulation has been implicated in the pathogenesis of microvascular complications in patients with T2DM. We sought to explore the diagnostic value of 5-hydroxymethylcytosines (5hmC) in circulating cell-free DNA (cfDNA) for DR, taking advantage of a highly sensitive technique, the 5hmC-Seal. The genome-wide 5hmC profiles in cfDNA samples from 35 patients diagnosed with DR and 35 age-, gender-, diabetic duration-matched T2DM controls were obtained using the 5hmC-Seal, followed by a case-control analysis and external validation. The genomic distribution of 5hmC in cfDNA from patients with DR reflected potential gene regulatory relevance, showing co localization with histone modification marks for active expression (e.g., H3K4me1). A three-gene signature (MESP1, LY6G6D, LINC01556) associated with DR was detected using the elastic net regularization on the multivariable logistic regression model, showing high accuracy to distinguish patients with DR from T2DM controls (AUC [area under curve] = 91.4%; 95% CI [confidence interval], 84.3- 98.5%), achieving a sensitivity of 88.6% and a specificity of 91.4%. In an external testing set, the 5hmC model detected 5 out of 6 DR patients and predicted 7 out of 8 non-DR patients with other microvascular complications. Circulating cfDNA from patients with DR contained 5hmC information that could be exploited for DR detection. As a novel non-invasive approach, the 5hmC-Seal holds the promise to be an integrated part of patient care and surveillance tool for T2DM patients.