title: Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes.
abstract: OBJECTIVE
  Increasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren's Syndrome (pSS). The aim of this study was to investigate the role of DNA methylation in pSS by analysing multiple tissues from patients and controls.
  
  
  METHODS
  Genome-wide DNA methylation profiles were generated using HumanMethylation450K BeadChips for whole blood, CD19+ B cells and minor salivary gland biopsies. Gene expression was analysed in CD19+ B cells by RNA-sequencing. Analysis of genetic regulatory effects on DNA methylation at known pSS risk loci was performed.
  
  
  RESULTS
  We identified prominent hypomethylation of interferon (IFN)-regulated genes in whole blood and CD19+ B cells, including at the genes MX1, IFI44L and PARP9, replicating previous reports in pSS, as well as identifying a large number of novel associations. Enrichment for genomic overlap with histone marks for enhancer and promoter regions was observed. We showed for the first time that hypomethylation of IFN-regulated genes in pSS B cells was associated with their increased expression. In minor salivary gland biopsies we observed hypomethylation of the IFN-induced gene OAS2. Pathway and disease analysis resulted in enrichment of antigen presentation, IFN signalling and lymphoproliferative disorders. Evidence for genetic control of methylation levels at known pSS risk loci was observed.
  
  
  CONCLUSIONS
  Our study highlights the role of epigenetic regulation of IFN-induced genes in pSS where replication is needed for novel findings. The association with altered gene expression suggests a functional mechanism for differentially methylated CpG sites in pSS aetiology.
authors: Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors: Juliana
authors: J
authors: Imgenberg-Kreuz
authors: Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors: Johanna K
authors: JK
authors: Sandling
authors: Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors: Jonas Carlsson
authors: JC
authors: Almlöf
authors: Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors: Jessica
authors: J
authors: Nordlund
authors: Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors: Linnea
authors: L
authors: Signér
authors: Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway.
authors: Katrine Braekke
authors: KB
authors: Norheim
authors: Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway.
authors: Roald
authors: R
authors: Omdal
authors: Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors: Lars
authors: L
authors: Rönnblom
authors: Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors: Maija-Leena
authors: ML
authors: Eloranta
authors: Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors: Ann-Christine
authors: AC
authors: Syvänen
authors: Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors: Gunnel
authors: G
authors: Nordmark
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics; D000328:Adult; D000368:Aged; D000941:Antigens / Q000235:genetics; D018941:Antigens, CD19 / Q000235:genetics; D016022:Case-Control Studies; D003598:Cytoskeletal Proteins / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D055106:Genome-Wide Association Study; D006801:Humans; D007372:Interferons / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D064547:Myxovirus Resistance Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D012470:Salivary Glands, Minor / Q000473:pathology; D012859:Sjogren's Syndrome / Q000097:blood / Q000235:genetics* / Q000473:pathology
chemical_list: D000941:Antigens; D018941:Antigens, CD19; D003598:Cytoskeletal Proteins; C065888:IFI44 protein, human; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D009363:Neoplasm Proteins; C418133:PARP9 protein, human; D007372:Interferons; D011065:Poly(ADP-ribose) Polymerases; C000607948:OAS2 protein, human; D015088:2',5'-Oligoadenylate Synthetase
keywords: Autoimmunity; B cells; Gene Polymorphism; Sjøgren's Syndrome