title: Identification of CpG-SNPs associated with type 2 diabetes and differential DNA methylation in human pancreatic islets.
abstract: OBJECTIVE
  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 (r² > 0.8) with a total of 295 SNPs, including 91 CpG-SNPs.
  
  
  CONCLUSIONS
  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.
authors: Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Scania University Hospital, Jan Waldenströmsgata 35, 205 02 Malmö, Sweden.
authors: T A
authors: TA
authors: Dayeh
authors: A H
authors: AH
authors: Olsson
authors: P
authors: P
authors: Volkov
authors: P
authors: P
authors: Almgren
authors: T
authors: T
authors: Rönn
authors: C
authors: C
authors: Ling
mesh_terms: D000368:Aged; D017398:Alternative Splicing; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D012537:Scandinavian and Nordic Countries; D046509:Tissue Culture Techniques; D014019:Tissue Donors
chemical_list: D007328:Insulin; D012333:RNA, Messenger