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

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          Abstract

          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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          Most cited references31

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          A genome-wide association study identifies novel risk loci for type 2 diabetes.

          Robert Sladek, Ghislain Rocheleau, Johan Rung … (2007)
          Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.
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            Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.

            Benjamin Voight, Laura J. Scott, Valgerdur Steinthorsdottir … (2010)
            By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
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              Conserved Role of Intragenic DNA Methylation in Regulating Alternative Promoters

              Alika Maunakea, Raman P. Nagarajan, Mikhail Bilenky … (2010)
              While the methylation of DNA in 5′ promoters suppresses gene expression, the role of DNA methylation in gene bodies is unclear 1–5 . In mammals, tissue- and cell type-specific methylation is present in a small percentage of 5′ CpG island (CGI) promoters, while a far greater proportion occurs across gene bodies, coinciding with highly conserved sequences 5–10 . Tissue-specific intragenic methylation might reduce, 3 or, paradoxically, enhance transcription elongation efficiency 1,2,4,5 . Capped analysis of gene expression (CAGE) experiments also indicate that transcription commonly initiates within and between genes 11–15 . To investigate the role of intragenic methylation, we generated a map of DNA methylation from human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were revealed to be in intragenic and intergenic regions, while less than 3% of CpG islands in 5′ promoters were methylated. The CpG islands in all three locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of H3K4, a histone modification enriched at promoters 16 . The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus 17,18 and its mouse homologue demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts are expressed in a tissue and cell type-specific manner, and are expressed differentially within a single cell type from distinct brain regions. These results support a major role for intragenic methylation in regulating cell context-specific alternative promoters in gene bodies.
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                Author and article information

                Contributors
                : charlotte.ling@med.lu.se
                Journal
                Journal ID (nlm-ta): Diabetologia
                Journal ID (iso-abbrev): Diabetologia
                Title: Diabetologia
                Publisher: Springer-Verlag (Berlin/Heidelberg )
                ISSN (Print): 0012-186X
                ISSN (Electronic): 1432-0428
                Publication date (Electronic): 6 March 2013
                Publication date PMC-release: 6 March 2013
                Publication date (Print): May 2013
                Volume: 56
                Issue: 5
                Pages: 1036-1046
                Affiliations
                [ ]Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Scania University Hospital, Jan Waldenströmsgata 35, 205 02 Malmö, Sweden
                [ ]Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Clinical Research Centre, Scania University Hospital, Jan Waldenströmsgata 35, 205 02 Malmö, Sweden
                Article
                Publisher ID: 2815
                DOI: 10.1007/s00125-012-2815-7
                PMC ID: 3622750
                PubMed ID: 23462794
                SO-VID: e02ee494-5c51-45dc-a24d-2fb6e9a19e47
                Copyright © © The Author(s) 2013
                License:

                Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                Date received : 14 November 2012
                Date accepted : 6 December 2012
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © Springer-Verlag Berlin Heidelberg 2013

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: alternative splicing,cpg-snp,dna methylation,epigenetics,glucagon,human pancreatic islets,insulin secretion,snp,splice index,type 2 diabetes
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: alternative splicing, cpg-snp, dna methylation, epigenetics, glucagon, human pancreatic islets, insulin secretion, snp, splice index, type 2 diabetes

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