Genome-wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy

BMC Medicine

Research Article

Eero Lindholm¹  Carl-David Agardh¹  Charlotte Ling²  Annika Lundstig²  Tina Rönn²  Petr Volkov²  Tove Freiburghaus²  Alexander Perfilyev²  Elisabet Agardh³ 

[1] Department of Clinical Sciences, Endocrinology, Lund University, Scania University Hospital, 205 02, Malmö, Sweden;Department of Clinical Sciences, Epigenetics and Diabetes Unit, Lund University Diabetes Centre, CRC, Scania University Hospital, 205 02, Malmö, Sweden;Department of Clinical Sciences, Ophthalmology, Lund University, Scania University Hospital, 205 02, Malmö, Sweden;

关键词: Diabetic complication;    DNA methylation;    Epigenetics;    Inflammation;    Prediction;    Proliferative retinopathy;    Prospective;    Type 1 diabetes;   

DOI  :  10.1186/s12916-015-0421-5

 received in 2014-11-03, accepted in 2015-07-15,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundEpigenetic 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).MethodsDNA 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.ResultsWe 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).ConclusionsSubjects 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.

【 授权许可】

Unknown   
© Agardh et al. 2015. This article is published under license to BioMed Central Ltd. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.