Genome-wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy.
Genome-wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy.
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DOI：
10.1186/s12916-015-0421-5
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发表时间：
2015-08-06
期刊：
影响因子：
9.3
通讯作者：
Ling C
中科院分区：
文献类型：
--
作者：
Agardh E;Lundstig A;Perfilyev A;Volkov P;Freiburghaus T;Lindholm E;Rönn T;Agardh CD;Ling C
表观遗传变异与几种人类疾病有关。糖尿病视网膜病变（PDR）是糖尿病患者视力丧失的主要原因。然而，缺乏研究PDR和全基因组DNA甲基化模式之间的关联。我们的目的是确定与1型糖尿病（T1 D）受试者PDR相关并预测PDR的表观遗传修饰。在来自PDR病例（n = 28）、对照（n = 30）和前瞻性队列（n = 7）的血液中的485，577个位点中分析了全基因组DNA甲基化。错误发现率分析用于校正多个测试的数据。在30岁之前诊断为T1 D且在诊断后1年内接受胰岛素治疗的研究参与者的选择基于1）归类为PDR的受试者（病例）和2）在血液DNA采样时患有糖尿病至少10年并在8.7年随访后归类为无/轻度糖尿病视网膜病变的T1 D受试者（对照）。还在一个前瞻性队列中分析了DNA甲基化，该队列包括7名T1 D受试者，他们在采集血液样本时没有/轻度糖尿病视网膜病变，但在6.3年内发生了PDR（转换者）。视网膜病变程度按眼底照相分级。我们鉴定了349个CpG位点的差异DNA甲基化，这些位点代表233个独特基因，包括TNF、CHI 3L 1（也称为YKL-40）、CHN 2、GIPR、GLRA 1、GPX 1、AHRR和BCOR。在PDR病例中，这些位点中的大多数（79%）显示DNA甲基化降低。在PDR病例中，发现自然杀伤细胞介导的细胞毒性途径在差异甲基化基因中显著富集（P = 0.006）。我们还在前瞻性队列中鉴定了代表17个基因（例如AHRR、GIPR、GLRA 1和BCOR）的28个CpG位点的差异DNA甲基化，P <0.05，这高于偶然预期（P = 0.0096）。患有T1 D和PDR的受试者在血液中表现出改变的DNA甲基化模式。这些表观遗传学变化中的一些可能预测PDR的发展，这表明DNA甲基化可以用作PDR的前瞻性标记。本文的在线版本（doi：10.1186/s12916-015-0421-5）包含补充材料，可供授权用户使用。
Epigenetic variation has been linked to several human diseases. Proliferative diabetic retinopathy (PDR) is a major cause of vision loss in subjects with diabetes. However, studies examining the association between PDR and the genome-wide DNA methylation pattern are lacking. Our aim was to identify epigenetic modifications that associate with and predict PDR in subjects with type 1 diabetes (T1D). DNA methylation was analyzed genome-wide in 485,577 sites in blood from cases with PDR (n = 28), controls (n = 30), and in a prospective cohort (n = 7). False discovery rate analysis was used to correct the data for multiple testing. Study participants with T1D diagnosed before 30 years of age and insulin treatment within 1 year from diagnosis were selected based on 1) subjects classified as having PDR (cases) and 2) subjects with T1D who had had diabetes for at least 10 years when blood DNA was sampled and classified as having no/mild diabetic retinopathy also after an 8.7-year follow-up (controls). DNA methylation was also analyzed in a prospective cohort including seven subjects with T1D who had no/mild diabetic retinopathy when blood samples were taken, but who developed PDR within 6.3 years (converters). The retinopathy level was classified by fundus photography. We identified differential DNA methylation of 349 CpG sites representing 233 unique genes including TNF, CHI3L1 (also known as YKL-40), CHN2, GIPR, GLRA1, GPX1, AHRR, and BCOR in cases with PDR compared with controls. The majority of these sites (79 %) showed decreased DNA methylation in cases with PDR. The Natural Killer cell-mediated cytotoxicity pathway was found to be significantly (P = 0.006) enriched among differentially methylated genes in cases with PDR. We also identified differential DNA methylation of 28 CpG sites representing 17 genes (e.g. AHRR, GIPR, GLRA1, and BCOR) with P <0.05 in the prospective cohort, which is more than expected by chance (P = 0.0096). Subjects with T1D and PDR exhibit altered DNA methylation patterns in blood. Some of these epigenetic changes may predict the development of PDR, suggesting that DNA methylation may be used as a prospective marker of PDR. The online version of this article (doi:10.1186/s12916-015-0421-5) contains supplementary material, which is available to authorized users.