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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.01686

Shared and unique patterns of DNA methylation in systemic lupus erythematosus and primary Sjögren’s syndrome

 Juliana Imgenberg-Kreuz1*, Jonas C. Almlöf2, Dag Leonard1,  Christopher Sjöwall3, Ann-Christine Syvänen2,  Lars Rönnblom1,  Johanna K. Sandling1 and  Gunnel Nordmark1
  • 1Department of Medical Sciences, Section of Rheumatology and Science for Life Laboratory, Uppsala University, Sweden
  • 2Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Sweden
  • 3Department of Clinical and Experimental Medicine, Rheumatology/Division of Neuro and Inflammation Sciences, Linköping University, Sweden

OBJECTIVES
To perform a cross-comparative analysis of DNA methylation in patients with systemic lupus erythematosus (SLE), patients with primary Sjögren’s syndrome (pSS) and healthy controls addressing the question of epigenetic sharing and aiming to detect disease-specific alterations.

METHODS
DNA extracted from peripheral blood from 347 cases with SLE, 100 cases with pSS and 400 healthy controls were analysed on the HumanMethylation 450k array, targeting 485,000 CpG sites across the genome. A linear regression model including age, sex and blood cell type distribution as covariates was fitted, and association p-values were Bonferroni corrected. A random forest machine learning classifier was designed for prediction of disease status based on DNA methylation data.

RESULTS
We established a combined set of 4,945 shared differentially methylated CpG sites (DMCs) in SLE and pSS compared to controls. In pSS, hypomethylation at type I interferon induced genes was mainly driven by patients who were positive for Ro/SSA and/or La/SSB autoantibodies. Analysis of differential methylation between SLE and pSS identified 2,244 DMCs with a majority of sites showing decreased methylation in SLE compared to pSS. The random forest classifier demonstrated good performance in discerning between disease status with an area under the curve (AUC) between 0.83 and 0.96.

CONCLUSIONS
The majority of differential DNA methylation is shared between SLE and pSS, however, important quantitative differences exist. Our data highlights neutrophil dysregulation as a shared mechanism, emphasizing the role of neutrophils in the pathogenesis of systemic autoimmune diseases. The current study provides evidence for genes and molecular pathways driving common and disease-specific pathogenic mechanisms.

Keywords: systemic lupus erythematosus (SLE), Primary Sjögren syndrome (pSS), DNA Methylation, EWAS, epigenetics, Type I interferon (IFN), Autoimmunity, Random forest prediction

Received: 12 Apr 2019; Accepted: 04 Jul 2019.

Edited by:

Claudio Lunardi, University of Verona, Italy

Reviewed by:

Richard Williams, University of Oxford, United Kingdom
Antonio Puccetti, University of Genoa, Italy  

Copyright: © 2019 Imgenberg-Kreuz, Almlöf, Leonard, Sjöwall, Syvänen, Rönnblom, Sandling and Nordmark. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Juliana Imgenberg-Kreuz, Uppsala University, Department of Medical Sciences, Section of Rheumatology and Science for Life Laboratory, Uppsala, Sweden, juliana.imgenberg@medsci.uu.se