Identification of Type 1 Diabetes–Associated DNA Methylation Variable Positions That Precede Disease Diagnosis

English version České info

Monozygotic (MZ) twin pair discordance for childhood-onset Type 1 Diabetes (T1D) is ∼50%, implicating roles for genetic and non-genetic factors in the aetiology of this complex autoimmune disease. Although significant progress has been made in elucidating the genetics of T1D in recent years, the non-genetic component has remained poorly defined. We hypothesized that epigenetic variation could underlie some of the non-genetic component of T1D aetiology and, thus, performed an epigenome-wide association study (EWAS) for this disease. We generated genome-wide DNA methylation profiles of purified CD14⁺ monocytes (an immune effector cell type relevant to T1D pathogenesis) from 15 T1D–discordant MZ twin pairs. This identified 132 different CpG sites at which the direction of the intra-MZ pair DNA methylation difference significantly correlated with the diabetic state, i.e. T1D–associated methylation variable positions (T1D–MVPs). We confirmed these T1D–MVPs display statistically significant intra-MZ pair DNA methylation differences in the expected direction in an independent set of T1D–discordant MZ pairs (P = 0.035). Then, to establish the temporal origins of the T1D–MVPs, we generated two further genome-wide datasets and established that, when compared with controls, T1D–MVPs are enriched in singletons both before (P = 0.001) and at (P = 0.015) disease diagnosis, and also in singletons positive for diabetes-associated autoantibodies but disease-free even after 12 years follow-up (P = 0.0023). Combined, these results suggest that T1D–MVPs arise very early in the etiological process that leads to overt T1D. Our EWAS of T1D represents an important contribution toward understanding the etiological role of epigenetic variation in type 1 diabetes, and it is also the first systematic analysis of the temporal origins of disease-associated epigenetic variation for any human complex disease.

Vyšlo v časopise: Identification of Type 1 Diabetes–Associated DNA Methylation Variable Positions That Precede Disease Diagnosis. PLoS Genet 7(9): e32767. doi:10.1371/journal.pgen.1002300
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002300

Souhrn

Zdroje

1. ToddJA 2010 Etiology of type 1 diabetes. Immunity 32 457 67

2. Wellcome Trust Case Control Consortium 2007 Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 661 78

3. LeslieRDDelli CastelliM 2004 Age-dependent influences on the origins of autoimmune diabetes: evidence and implications. Diabetes 53 3033 40

4. BachJF 2002 The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347 911 20

5. RedondoMJYuLHawaMMackenzieTPykeDA 2001 Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States. Diabetologia 44 354 62

6. HyttinenVKaprioJKinnunenLKoskenvuoMTuomilehtoJ 2003 Genetic liability of type 1 diabetes and the onset age among 22,650 young Finnish twin pairs: a nationwide follow-up study. Diabetes 52 1052 5

7. KnipMVeijolaRVirtanenSMHyötyHVaaralaO 2005 Environmental triggers and determinants of type 1 diabetes. Diabetes 54 Suppl 2 S125 36

8. JaenischRBirdA 2003 Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33 Suppl 245 54

9. FragaMFBallestarEPazMFRoperoSSetienF 2005 Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 10 10604 9

10. JavierreBMFernandezAFRichterJAl-ShahrourFMartin-SuberoJI 2010 Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res 20 170 9

11. KaminskyZATangTWangSCPtakCOhGH 2009 DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41 240 5

12. NguyenARauchTAPfeiferGPHuVW 2010 Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain. FASEB J Apr 7. (Epub ahead of print)

13. FeinbergAPIrizarryRAFradinDAryeeMJ 2010 Personalized epigenomic signatures that are stable over time and covary with body mass index. Sci Transl Med 2 49ra67

14. BellCGTeschendorffAERakyanVKMaxwellAPBeckS 2010 Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus. BMC Med Genomics 5 33 7

15. BellCGFinerSLindgrenCMWilsonGARakyanVK 2010 Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. PLoS One 5 e14040

16. BluestoneJAHeroldKEisenbarthG 2010 Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464 1293 300

17. UnoSImagawaAOkitaKSayamaKMoriwakiM 2007 Macrophages and dendritic cells infiltrating islets with or without beta cells produce tumour necrosis factor-alpha in patients with recent-onset type 1 diabetes. Diabetologia 50 596 601

18. LitherlandSAXieXTHutsonADWasserfallCWhittakerDS 1999 Aberrant prostaglandin synthase 2 expression defines an antigen-presenting cell defect for insulin-dependent diabetes mellitus. J Clin Invest 104 515 23

19. BeyanHGoodierMRNawrolyNSHawaMI 2006 Altered monocyte cyclooxygenase response to lipopolysaccharide in type 1 diabetes. Diabetes 55 3439 45

20. BibikovaMLeJBarnesBSaedinia-MelnykSZhouL 2009 Genome-wide DNA methylation profiling using Infinium® assay. Epigenomics 1 177 200

21. EckhardtFLewinJCorteseRRakyanVKAttwoodJ 2006 DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet 38 1378 85

22. DejeuxEAudardVCavardCGutIGTerrisBTostJ 2007 Rapid identification of promoter hypermethylation in hepatocellular carcinoma by pyrosequencing of etiologically homogeneous sample pools. J Mol Diagn 9 510 20

23. ClaytonDG 2009 Prediction and interaction in complex disease genetics: experience in type 1 diabetes. PLoS Genet 5 e1000540

24. LudvigssonJFaresjöMHjorthMAxelssonSChéramyM 2008 GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med 359 1909 20

25. BoehmBOManfrasBSeisslerJSchöfflingKGlückM 1991 Epidemiology and immunogenetic background of islet cell antibody positive nondiabetic schoolchildren. Ulm-Frankfurt population study. Diabetes 40 1435 9

26. GardnerSGGaleEAWilliamsAJGillespieKMLawrenceKE 1999 Progression to diabetes in relatives with islet autoantibodies. Is it inevitable? Diabetes Care 22 2049 54

27. OresicMSimellSSysi-AhoMNäntö-SalonenKSeppänen-LaaksoT 2008 Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. J Exp Med 205 2975 84

28. RakyanVKBlewittMEDrukerRPreisJIWhitelawE 2002 Metastable epialleles in mammals. Trends Genet 18 348 51

29. RichardsEJ 2006 Inherited epigenetic variation–revisiting soft inheritance. Nat Rev Genet 7 395 401

30. FeinbergAPIrizarryRA 2010 Evolution in health and medicine Sackler colloquium: Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease. Proc Natl Acad Sci U S A Suppl 11757 64

31. KnipMVirtanenSMSeppäKIlonenJSavilahtiEVaaralaO 2010 Dietary intervention in infancy and later signs of beta-cell autoimmunity. N Engl J Med 363 1900 8

32. ManolioTACollinsFSCoxNJGoldsteinDBHindorffLAHunterDJMcCarthyMIRamosEMCardonLRChakravartiAChoJHGuttmacherAEKongAKruglyakLMardisERotimiCNSlatkinMValleDWhittemoreASBoehnkeMClarkAGEichlerEEGibsonGHainesJLMackayTFMcCarrollSAVisscherPM 2009 Finding the missing heritability of complex diseases. Nature 461 747 53

33. RakyanVKDownTABaldingDJBeckS 2011 Epigenome-wide association studies for common human diseases. Nat Rev Genet 12 529 41

34. HawaMRoweRLanMSNotkinsALPozzilliP 1997 Value of antibodies to islet protein tyrosine phosphatase-like molecule in predicting type 2 diabetes. Diabetes 46 1270 5

35. WenzlauJMJuhlKYuL 2007 The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A 104 17040 5