title: Epigenome-wide DNA methylation patterns associated with fatigue in primary Sjögren's syndrome.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway katnorheim@gmail.com.
authors.forename: Katrine
authors.initials: K
authors.lastname: Brække Norheim
authors.affiliation: Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Juliana
authors.initials: J
authors.lastname: Imgenberg-Kreuz
authors.affiliation: Department of Pathology, Stavanger University Hospital, Stavanger, Norway.
authors.forename: Kristin
authors.initials: K
authors.lastname: Jonsdottir
authors.affiliation: Department of Pathology, Stavanger University Hospital, Stavanger, Norway.
authors.forename: Emiel A M
authors.initials: EA
authors.lastname: Janssen
authors.affiliation: Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.affiliation: Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Johanna K
authors.initials: JK
authors.lastname: Sandling
authors.affiliation: Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Gunnel
authors.initials: G
authors.lastname: Nordmark
authors.affiliation: Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway.
authors.forename: Roald
authors.initials: R
authors.lastname: Omdal
mesh_terms: D000328:Adult; D000368:Aged; D003597:Cytosine Nucleotides / Q000235:genetics; D019175:DNA Methylation; D057890:Epigenomics; D015673:Fatigue Syndrome, Chronic / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D012859:Sjogren's Syndrome / Q000150:complications* / Q000235:genetics
chemical_list: D003597:Cytosine Nucleotides
keywords: DNA methylation; epigenetics; fatigue; primary Sjögren’s syndrome