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Shared and Unique Patterns of DNA Methylation in Systemic Lupus Erythematosus and Primary Sjogrens Syndrome
Uppsala Univ, Sweden.
Uppsala Univ, Sweden.
Uppsala Univ, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.ORCID iD: 0000-0003-0900-2048
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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 Sjogrens 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 Sjogrens syndrome; DNA methylation; EWAS; epigenetics; autoimmunity; type I interferon; random forest
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-159569DOI: 10.3389/fimmu.2019.01686ISI: 000477805800001OAI: oai:DiVA.org:liu-159569DiVA, id: diva2:1342423
Note

Funding Agencies|Knut and Alice Wallenberg Foundation [KAW 2011.0073]; Swedish Research Council for Medicine and Health [VR-MH Dnr 521-2014-2263, Dnr 2018-02399, Dnr 2016-01982]; Gustaf V and Queen Victorias Freemasons Foundation; County Council of Ostergotland; Swedish Rheumatism Association; King Gustaf Vs 80-year Foundation; Swedish Society of Medicine; Science for Life Laboratory, Uppsala University; Swedish Research Council (VR-RFI); Ingegerd Johansson donation; Knut and Alice Wallenberg Foundation

Available from: 2019-08-13 Created: 2019-08-13 Last updated: 2019-11-18

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Sjöwall, Christopher
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Division of Neuro and Inflammation ScienceFaculty of Medicine and Health SciencesDepartment of Rheumatology
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