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      Different Methylation of CpG-SNPs in Behcet's Disease

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          Abstract

          Purpose

          We recently performed an Epigenome-Wide Association Studies (EWAS) study in Behcet's disease (BD) and identified various cytosine–phosphate–guanine (CpG) loci that were aberrantly methylated. In the current study, we wanted to investigate whether these sites contained genetic polymorphisms and whether the frequency of these polymorphisms was altered in BD.

          Methods

          A two-stage study was performed. The first stage involved 358 BD patients and 704 healthy controls to investigate genetic variants of 10 CpG-SNPs (rs10454134, rs176249, rs3808620, rs10176517, rs11247118, rs78016579, rs9461624, rs10492166, rs34929465, and rs6507921) using an iPLEX Gold genotyping assay and a Sequenom MassARRAY. In the second stage, an additional 172 independent BD patients and 330 healthy individuals are to confirm trends found in the first stage.

          Results

          A higher frequency of both the rs10454134 AG genotypes (p = 0.008, OR = 1.413, 95% CI = 1.094-1.826) and a lower GG genotype frequency (p = 0.003, OR = 0.630, 95% CI = 0.465-0.854) were found in BD patients compared to the controls in the first stage. However, after correcting for multiple comparisons, all associations identified in the first stage lost statistical significance. The frequencies of the other CpG-SNPs investigated were not different between BD patients and controls. The second stage was designed using an additional cohort to confirm the association with CpG-SNP, rs10454134. The data failed to confirm the association between this CpG-SNP and BD.

          Conclusions

          This study did not show an association between BD and CpG-SNPs in gene sites that were earlier shown to be aberrantly methylated.

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          Most cited references23

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          Criteria for diagnosis of Behcet's disease

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            Identification of CpG-SNPs associated with type 2 diabetes and differential DNA methylation in human pancreatic islets

            Aims/hypothesis To date, the molecular function of most of the reported type 2 diabetes-associated loci remains unknown. The introduction or removal of cytosine–phosphate–guanine (CpG) dinucleotides, which are possible sites of DNA methylation, has been suggested as a potential mechanism through which single-nucleotide polymorphisms (SNPs) can affect gene function via epigenetics. The aim of this study was to examine if any of 40 SNPs previously associated with type 2 diabetes introduce or remove a CpG site and if these CpG-SNPs are associated with differential DNA methylation in pancreatic islets of 84 human donors. Methods DNA methylation was analysed using pyrosequencing. Results We found that 19 of 40 (48%) type 2 diabetes-associated SNPs introduce or remove a CpG site. Successful DNA methylation data were generated for 16 of these 19 CpG-SNP loci, representing the candidate genes TCF7L2, KCNQ1, PPARG, HHEX, CDKN2A, SLC30A8, DUSP9, CDKAL1, ADCY5, SRR, WFS1, IRS1, DUSP8, HMGA2, TSPAN8 and CHCHD9. All analysed CpG-SNPs were associated with differential DNA methylation of the CpG-SNP site in human islets. Moreover, six CpG-SNPs, representing TCF7L2, KCNQ1, CDKN2A, ADCY5, WFS1 and HMGA2, were also associated with DNA methylation of surrounding CpG sites. Some of the type 2 diabetes CpG-SNP sites that exhibit differential DNA methylation were further associated with gene expression, alternative splicing events determined by splice index, and hormone secretion in the human islets. The 19 type 2 diabetes-associated CpG-SNPs are in strong linkage disequilibrium (r 2 > 0.8) with a total of 295 SNPs, including 91 CpG-SNPs. Conclusions/interpretation Our results suggest that the introduction or removal of a CpG site may be a molecular mechanism through which some of the type 2 diabetes SNPs affect gene function via differential DNA methylation and consequently contributes to the phenotype of the disease. Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2815-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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              Dependence of transcriptional repression on CpG methylation density.

              C L Hsieh (1994)
              CpG methylation is known to suppress transcription. This repression is generally thought to be related to alterations of chromatin structure that are specified by the methylation. The nature of these chromatin alterations is unknown. Moreover, it has not been clear if the methylation repression occurs in an all-or-none fashion at some critical methylation density, or if intermediate densities of methylation can give intermediate levels of repression. Here I report a stable episomal system which recapitulates many dynamic features of methylation observed in the genome. I have determined the extent of transcriptional repression as a function of four densities of CpG methylation. I find that the repression is a graded but exponential function of the CpG methylation density such that low levels of methylation yield a 67 to 90% inhibition of gene expression. Higher levels of methylation extinguished gene expression completely. Transcription from methylated minichromosomes can be increased by butyrate treatment, suggesting that histone acetylation can reverse some of the repression specified by the methylated state. Sites of preferential demethylation occurred and may have resulted from transcription factor binding or DNA looping.
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                Author and article information

                Contributors
                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi
                2314-6133
                2314-6141
                2019
                16 May 2019
                : 2019
                : 3489305
                Affiliations
                The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, China
                Author notes

                Academic Editor: Heide Schatten

                Author information
                http://orcid.org/0000-0002-7761-9819
                http://orcid.org/0000-0001-6252-5628
                http://orcid.org/0000-0002-5455-0791
                http://orcid.org/0000-0001-6411-3643
                http://orcid.org/0000-0002-2647-6619
                Article
                10.1155/2019/3489305
                6541967
                01b6f682-0e32-481d-98df-9cd57bbfbc74
                Copyright © 2019 Yang Huang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 18 January 2019
                : 4 May 2019
                : 7 May 2019
                Funding
                Funded by: National Key R&D Program of China
                Award ID: 2016YFC0904000
                Funded by: Natural Science Foundation Major International (Regional) Joint Research Project
                Award ID: 81720108009
                Funded by: Chongqing Key Laboratory of Ophthalmology
                Award ID: 2008CA5003
                Funded by: Chongqing Science & Technology Platform and Base Construction Program
                Award ID: cstc2014pt-sy10002
                Funded by: Natural Science Foundation Project of Chongqing
                Award ID: cstc2017shmsA130073
                Categories
                Research Article

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