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Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes
  1. Juliana Imgenberg-Kreuz1,
  2. Johanna K Sandling1,2,
  3. Jonas Carlsson Almlöf1,
  4. Jessica Nordlund1,
  5. Linnea Signér2,
  6. Katrine Braekke Norheim3,
  7. Roald Omdal3,
  8. Lars Rönnblom2,
  9. Maija-Leena Eloranta2,
  10. Ann-Christine Syvänen1,
  11. Gunnel Nordmark2
  1. 1Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  2. 2Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  3. 3Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway
  1. Correspondence to Dr Gunnel Nordmark, Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala SE-751 85, Sweden; Gunnel.Nordmark{at}


Objectives 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.

  • Sjøgren's Syndrome
  • B cells
  • Autoimmunity
  • Gene Polymorphism

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  • Handling editor Tore K Kvien

  • JI-K and JKS contributed equally.

  • Contributors JI-K, JKS, KBN, RO, A-CS and GN designed the study; LS, LR, M-LE and GN collected patient and control material and clinical data; JI-K and JKS performed the experiments; JI-K, JKS, JCA and JN analysed the data; JI-K, JKS and GN drafted the manuscript and all authors read and accepted the final version of the manuscript. JI-K and JKS contributed equally to the study.

  • Funding This study was supported by grants from the Knut and Alice Wallenberg Foundation, the Swedish Research Council for Medicine and Health (Dnr 521-2014-2263 ACS and Dnr 521-2013-2830 LR), the Gustav V: 80-year Foundation, Combine, the Swedish Society of Medicine and the Swedish Rheumatism Association. JKS was supported by a Swedish Research Council postdoc grant (Dnr 350-2012-256). The SNP&SEQ Technology Platform is supported by the Swedish Research Council (VR-RFI), Science for Life Laboratory and the Knut and Alice Wallenberg Foundation.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the Regional Ethics board in Uppsala No. 97358, 217/2006 and 013/2009.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Normalised or raw intensity data of the HM450K BeadChips are available upon request from the authors on a collaborative basis.

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