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Genome-Wide Analysis of DNA Methylation

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Genome-Wide Analysis of DNA Methylation Li et al. Clinical Epigenetics (2020) 12:77 https://doi.org/10.1186/s13148-020-00871-z RESEARCH Open Access Genome-wide analysis of DNA methylation identifies S100A13 as an epigenetic biomarker in individuals with chronic (≥ 30 years) type 2 diabetes without diabetic retinopathy Tao Li1,2,YiXu1,2, Yongyong Shi3, Jianhua Chen4, Senlin Lin1,2, Jianfeng Zhu1,2, Xian Xu1,2, Lina Lu1,2 and Haidong Zou1,2* Abstract Background: This study aimed to determine the epigenetic biomarkers of diabetic retinopathy (DR) in subjects with type 2 diabetes mellitus (T2DM). This retrospective study is based on the Shanghai Xinjing community prevention and treatment administrative system of chronic diseases. The subjects enrolled herein were T2DM patients who had undergone long-term follow-up evaluation in the system. Two consecutive studies were conducted. In the discovery cohort, among 19 subjects who had developed DR with a DM duration < 3 years and 21 subjects without DR > 30 years after being diagnosed with DM, an Infinium Human Methylation 850 Beadchip was used to identify differential methylation regions (DMRs) and differential methylation sites (DMSs). The function of the genes was assessed through KEGG enrichment analysis, Gene Ontology (GO) analysis, and pathway network analysis. In the replication cohort, 87 DR patients with a short DM duration and 89 patients without DR over a DM duration > 20 years were compared to assess the association between DMSs and DR upon pyrosequencing. Results: A total of 34 DMRs were identified. Genes containing DMSs with the top 5 highest beta value differences between DR and non-DR participants were located on chromosome 1 and were present in the S100A13 gene, which was associated with 71 GO terms. Two S100A13 gene sites, i.e., cg02873163 and cg11343894, displayed a good correlation with DR on pyrosequencing. Conclusions: DMSs in the S100A13 gene may be potential biomarkers of DR. Keywords: Diabetic retinopathy, T2DM, Biomarkers, DNA methylation, S100A13 Background mellitus (DM) [1, 2]. Furthermore, hyperglycemia can Epigenetic determinants reportedly contribute to the eti- affect DNA methylase activity or the methylation level of ology of numerous systemic disorders such as diabetes specific genes, which is the primary epigenetic modifica- tion [3–7]. Diabetic retinopathy (DR) is a common com- * Correspondence: [email protected] plication of DM and a leading cause of blindness among 1Shanghai Eye Diseases Prevention & Treatment Center/Shanghai Eye – Hospital, No. 380, Kangding Road, Shanghai 200040, China individuals aged 20 62 years in developed countries [8]. 2Department of Ophthalmology, Shanghai General Hospital, Shanghai However, the exact etiology of DR remains unclear. Jiaotong University School of Medicine, Shanghai, China Chen et al. reported that approximately 300 differential Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data. Li et al. Clinical Epigenetics (2020) 12:77 Page 2 of 10 methylation sites (DMSs) in DNA were associated with for differences in the duration and hemoglobin A1C DR onset in type 1 DM (T1DM) patients [9]. Agardh (HbA1c) levels, the two groups did not significantly dif- et al. reported an association between DNA methylation fer in age, sex, glucose levels, body mass index (BMI), and proliferative DR among individuals with T1DM [5]. spherical equivalent rate, intraocular pressure, or axial However, among individuals with T2DM, no specific length. In the DR group, one had proliferative DR, 5 pa- gene methylation levels have been reported to be associ- tients had severe nonproliferative DR, and 13 patients ated with DR, even in PubMed. had moderate nonproliferative DR. Diabetic macular In the present study, we assessed the epigenetic edema was detected in 3 patients. The 21 non-DR sub- biomarkers of DR in T2DM patients. In the discov- jects did not present signs of DR on annual eye examin- ery cohort, among 19 subjects who developed DR ation after they were diagnosed with T2DM. The with a DM duration of < 3 years and 21 subjects duration of DM among these subjects was > 30 years. without DR > 30 years after being diagnosed with We identified thirty-four differential methylation re- DM, > 850,000 gene sites were assessed with a gions (DMRs) when comparing the DR group and non- methylation chip. The functions of genes harboring DR group. The DMRs comprised 11 hypermethylated re- DMSs with different degrees of methylation between gions and 23 hypomethylated regions. Of the 12 gene- the DR and non-DR participants were assessed related sites, two DMSs were located at the transcrip- through KEGG enrichment analysis, Gene Ontology tional start site (TSS) 1500, one at TSS 200, one in the (GO) analysis, and pathway network analysis and 5′-untranslated region UTR-5, three in EXON1, two in assessed for their association with DR. In the repli- the gene body, and three in the 3′-UTR (Table 2). cation cohort, 87 DR patients with a short DM dur- Global DNA methylation levels did not significantly ation and 89 patients without DR over a DM differ between the DR group and the non-DR group (P > duration > 20 years were compared to validate the 0.05). Furthermore, among 290 DMSs, methylation association between the DMSs identified in the dis- levels were decreased at 188 sites and increased at the covery cohort and DR through pyrosequencing. other 102 sites in the DR group (Supplement 1). These DMSs were evenly distributed on all chromosomes (Fig. Results 1). The genes containing DMSs with the top 5 differ- Discovery study ences in beta values between DR and non-DR partici- The basic and clinical characteristics of the 19 DR and pants are listed in Table 3; these DMSs were detected in 21 non-DR subjects are summarized in Table 1. Except the S100A13 gene. On GO enrichment analysis and KEGG pathway Table 1 The basic and clinical characteristics of the 19 diabetic analysis (Supplement 2 and 3, respectively), the top retinopathy patients (type 2 diabetes mellitus duration of < 3 30 items are summarized in Fig. 2 aandb,respect- years) and 21 patients with no sign of diabetic retinopathy with ively. DR-associated pathways included the Wnt sig- a type 2 diabetes mellitus duration of > 30 years enrolled in the discovery study naling pathway, ubiquitin-mediated proteolysis, Toll- like receptor signaling pathway, tight junctions, the Characteristics* DR group Non-DR group P value# transforming growth factor-beta signaling pathway, Number 19 21 / the phosphatidylinositol signaling pathway, natural Sex (male) 10 10 1 killer cell-mediated cytotoxicity, inositol phosphoryl- Age (year) 68.74 ± 8.69 74.19 ± 8.59 0.05 ation metabolism, the hedgehog signaling pathway, Age of DM onset (year) 67.26 ± 8.59 40.10 ± 9.13 0.00 aminoglycan degradation, Fcγ receptor-mediated au- DM duration (year) 1.47 ± 1.07 34.09 ± 5.74 / tophagy, cell adhesion factor signaling, the calcium Blood glucose (mmol/L) 6.95 ± 1.94 6.99 ± 2.22 0.93 signaling pathway, regulation of muscle contraction, neural tube formation, neural cell development, iron HbA1c (%) 6.79 ± 1.26 7.53 ± 1.44 0.04 ion balance, fibroblast proliferation, phagocytosis as- 2 BMI (kg/m ) 25.30 ± 4.55 24.94 ± 3.33 0.94 sociated with Fcγ receptor pathogenesis, glucose- MAP (mmHg) 102.98 ± 12.53 103.37 ± 13.45 0.93 stimulated cellular responses, and developmental SER (D) − 0.53 ± 2.06 0.17 ± 2.01 0.24 processes. Differential methylation in apoptotic re- IOP (mmHg) 13.80 ± 4.24 15.02 ± 2.62 0.28 sponses and genes involved in AMPK activity are in- AL (mm) 23.23 ± 1.13 23.26 ± 0.86 0.93 dicated in Fig. 2 a, b, and c. S100A13 was associated with 71 GO terms, including signal transduction and DR diabetic retinopathy, T2DM type 2 diabetes mellitus *BMI body mass index; MAP (mmHg) mean arterial pressure, equal to (systolic calcium ion binding, which are reportedly associated pressure + 2*diastolic pressure)/3; SER (D) spherical equivalent rate, equal to with DR pathogenesis [10, 11]. Therefore, the DMSs spherical power + 1/2 cylindrical power; IOP: intraocular pressure; AL: axial length. of the S100A13 gene were considered candidate #X2 Chi-square test, t Student’s t test, Z Mann-Whitney test DMSs. Li et al. Clinical Epigenetics (2020) 12:77 Page 3 of 10 Table 2 Differential methylation regions corresponding genes and β values of diabetic retinopathy and nondiabetic retinopathy subjects in the discovery study DMR Gene β value P value DR group Non-DR group Difference TSS1500 MDFI 0.414024
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