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Epigenome-wide DNA methylation patterns associated with fatigue in primary Sjogren's syndrome
Stavanger Univ Hosp, Clin Immunol Unit, Dept Internal Med, Pb 8100 Forus, N-4068 Stavanger, Norway..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
Stavanger Univ Hosp, Dept Pathol, N-4068 Stavanger, Norway..
Stavanger Univ Hosp, Dept Pathol, N-4068 Stavanger, Norway..
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2016 (English)In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 55, no 6, 1074-1082 p.Article in journal (Refereed) Published
Resource type
Text
Abstract [en]

Objective. Chronic fatigue is a common, disabling and poorly understood phenomenon. Recent studies indicate that epigenetic mechanisms may be involved in the expression of fatigue, a prominent feature of primary SS (pSS). The aim of this study was to investigate whether DNA methylation profiles of whole blood are associated with fatigue in patients with pSS. Methods. Forty-eight pSS patients with high (n = 24) or low (n = 24) fatigue as measured by a visual analogue scale were included. Genome-wide DNA methylation was investigated using the Illumina HumanMethylation450 BeadChip array. After quality control, a total of 383 358 Cytosine-phosphate-Guanine (CpG) sites remained for further analysis. Age, sex and differential cell count estimates were included as covariates in the association model. A false discovery rate-corrected P < 0.05 was considered significant, and a cut-off of 3% average difference in methylation levels between high- and low-fatigue patients was applied. Results. A total of 251 differentially methylated CpG sites were associated with fatigue. The CpG site with the most pronounced hypomethylation in pSS high fatigue annotated to the SBF2-antisense RNA1 gene. The most distinct hypermethylation was observed at a CpG site annotated to the lymphotoxin alpha gene. Functional pathway analysis of genes with differently methylated CpG sites in subjects with high vs low fatigue revealed enrichment in several pathways associated with innate and adaptive immunity. Conclusion. Some genes involved in regulation of the immune system and in inflammation are differently methylated in pSS patients with high vs low fatigue. These findings point to functional networks that may underlie fatigue. Epigenetic changes could constitute a fatigue-regulating mechanism in pSS.

Place, publisher, year, edition, pages
2016. Vol. 55, no 6, 1074-1082 p.
Keyword [en]
primary Sjogren's syndrome, epigenetics, DNA methylation, fatigue
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:uu:diva-299502DOI: 10.1093/rheumatology/kew008ISI: 000377432200015OAI: oai:DiVA.org:uu-299502DiVA: diva2:949694
Available from: 2016-07-22 Created: 2016-07-22 Last updated: 2016-12-14Bibliographically approved
In thesis
1. Epigenetic and Gene Expression Signatures in Systemic Inflammatory Autoimmune Diseases
Open this publication in new window or tab >>Epigenetic and Gene Expression Signatures in Systemic Inflammatory Autoimmune Diseases
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Autoimmune diseases are clinical manifestations of a loss-of-tolerance of the immune system against the body’s own substances and healthy tissues. Primary Sjögren’s syndrome (pSS) and systemic lupus erythematosus (SLE) are two chronic inflammatory autoimmune diseases characterized by autoantibody production and an activated type I interferon system. Although the precise mechanisms leading to autoimmune processes are not well defined, recent studies suggest that aberrant DNA methylation and gene expression patterns may play a central role in the pathogenesis of these disorders. The aim of this thesis was to investigate DNA methylation and gene expression in pSS and SLE on a genome-wide scale to advance our understanding of how these factors contribute to the diseases and to identify potential biomarkers and novel treatment targets.

In study I, differential DNA methylation was analyzed in multiple tissues from pSS patients and healthy controls. We identified thousands of CpG sites with perturbed methylation; the most prominent finding was a profound hypomethylation at regulatory regions of type I interferon induced genes in pSS. In study II, a cases-case study comparing DNA methylation in pSS patients with high fatigue to patients with low fatigue, we found methylation patterns associated to the degree of fatigue. In study III, RNA-sequencing was applied to investigate the transcriptome of B cells in pSS in comparison to controls. Increased expression of type I and type II interferon regulated genes in pSS was observed, indicating ongoing immune activation in B cells. In study IV, the impact of DNA methylation on disease susceptibility and phenotypic variability in SLE was investigated. We identified DNA methylation patterns associated to disease susceptibility, SLE manifestations and different treatments. In addition, we mapped methylation quantitative trait loci and observed evidence for genetic regulation of DNA methylation in SLE.  

In conclusion, the results presented in this thesis provide new insights into the molecular mechanisms underlying autoimmunity in pSS and SLE. The studies confirm the central role of the interferon system in pSS and SLE and further suggest novel genes and mechanisms to be involved in the pathogenesis these autoimmune diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1286
Keyword
Autoimmunity, DNA methylation, Primary Sjögren’s syndrome, Systemic lupus erythematosus, Gene expression, Type I interferon system, Epigenetics
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-310388 (URN)978-91-554-9782-8 (ISBN)
Public defence
2017-02-17, Enghoffsalen, entrance 50, ground floor, Uppsala University Hospital, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2017-01-26 Created: 2016-12-14 Last updated: 2017-02-01

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