Background/Purpose: Sjögren’s Syndrome (SS, OMIM #270150) is a chronic, multi-system autoimmune disease characterized by progressive destruction of the exocrine glands, with subsequent mucosal and conjunctival dryness. A growing body of evidence indicates that many epigenetic changes are associated with disease status and that epigenetic marks can provide unique insights into complex disease mechanisms. We report on results of a case-control study of DNA methylation (DNAm) differences within labial salivary gland tissue, using biopsies sampled from 13 severe SS cases and 13 controls in the Sjögren’s International Collaborative Clinical Alliance (SICCA; http://sicca.ucsf.edu/; HHSN268201300057C) registry.

Methods: We have methylotyped gland tissue and sorted PBMCs from these subjects using the Illumina HumanMethylation450 (450k) BeadChip platform. In addition to standard background correction and normalization techniques, we applied an adaptive normalization scheme to adjust for residual associations between DNAm and control measures. 

Results: Principal component analysis (PCA), applied to the 404,353 CpG sites passing strict QC criteria, clearly distinguishes glands of primary SS cases from those of controls. We find over 10,000 significant differentially methylated positions (DMPs) that show significant overlap with the promoters of genetic risk loci as a whole, with particular enrichment seen in the promoters of CXCR5 and BLK. We also observe an extended region of differential methylation surrounding PSMB8 and TAP1 in the MHC class II region. Despite a previous report of association between global DNAm and ICAM1 expression in the context of SS, we fail to detect differential methylation in the promoter of the ICAM1 locus. On the other hand, differential methylation patterns surrounding several non-coding RNAs suggest many indirect consequences of the observed salivary gland hypo-methylation in SS. Transcription factor motif enrichment analysis highlights the specific nature of these methylation differences, demonstrating co-localization of DMPs with interferon- stimulated response element (ISRE) and PU-Box motifs. DNAm signatures derived from sorted PBMCs show that disease-associated changes in DNAm are linearly correlated with cell-type specific patterns, resolving differential lymphocyte proportions. 

Conclusion: Our results emphasize the utility of CpG methylation not only as a biomarker of disease status, but also as an independent probe of underlying disease processes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-dna-methylation-signatures-of-salivary-gland-inflammation-in-sjogrens-syndrome/