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Shared and Unique Patterns of DNA Methylation in Systemic Lupus Erythematosus and Primary Sjogren's Syndrome
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.ORCID iD: 0000-0002-7230-8990
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Linkoping Univ, Dept Clin & Expt Med, Div Neuro & Inflammat Sci, Rheumatol, Linkoping, Sweden.
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1686Article in journal (Refereed) Published
Abstract [en]

Objectives: To performa cross-comparative analysis of DNA methylation in patients with systemic lupus erythematosus (SLE), patients with primary Sjogren'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 analyzed on the Human Methylation 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 highlight 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.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA , 2019. Vol. 10, article id 1686
Keywords [en]
systemic lupus erythematosus, primary Sjogren's syndrome, DNA methylation, EWAS, epigenetics, autoimmunity, type I interferon, random forest
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:uu:diva-391357DOI: 10.3389/fimmu.2019.01686ISI: 000477805800001PubMedID: 31428085OAI: oai:DiVA.org:uu-391357DiVA, id: diva2:1354240
Funder
Knut and Alice Wallenberg Foundation, KAW 2011.0073Swedish Research Council, VR-MH Dnr 521-2014-2263Swedish Research Council, Dnr 2018-02399Swedish Research Council, Dnr 2016-01982Swedish Research CouncilKnut and Alice Wallenberg FoundationAvailable from: 2019-09-24 Created: 2019-09-24 Last updated: 2019-09-24Bibliographically approved

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Imgenberg-Kreuz, JulianaCarlsson Almlöf, JonasLeonard, DagSyvänen, Ann-ChristineRönnblom, LarsSandling, Johanna K.Nordmark, Gunnel

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