期刊
DIABETOLOGIA
卷 56, 期 5, 页码 1036-1046出版社
SPRINGER
DOI: 10.1007/s00125-012-2815-7
关键词
Alternative splicing; CpG-SNP; DNA methylation; Epigenetics; Glucagon; Human pancreatic islets; Insulin secretion; SNP; Splice index; Type 2 diabetes
资金
- Nordic Network for Clinical Islet Transplantation (JDRF) [31-2008-413]
- Swedish Research Council, Region Skane
- Knut and Alice Wallenberg Foundation
- Novo Nordisk Foundation
- Soderberg, Diabetes Fonden, Pahlsson, Linne [B31 5631/2006]
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.
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