Distinct Patterns of DNA Methylation in Labial Salivary Gland Tissue Based on Sjögren’s Syndrome Disease Status

Michael Cole¹, Xiaorong Shao¹, Diana Quach², Hong L. Quach², Lisa F. Barcellos² and Lindsey A. Criswell³, ¹Genetic Epidemiology and Genomics Lab, Division of Epidemiology, University of California, Berkeley, Berkeley, CA, ²Epidemiology, University of California, Berkeley, Berkeley, CA, ³Medicine, University of California, San Francisco, Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, San Francisco, CA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: DNA Methylation, epigenetics and salivary gland, Sjogren's syndrome

Session Information

Title: Sjogren's Syndrome: Pathophysiology

Session Type: Abstract Submissions (ACR)

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 epigenetic changes contribute to the development of this complex disease. In particular, altered patterns of DNA methylation may modulate both risk and severity.

Methods

We report an expanded case-control study of DNA methylation differences within labial salivary gland tissues, using biopsies sampled from 12 primary SS cases, 2 secondary SS cases, and 14 controls in the Sjögren’s International Collaborative Clinical Alliance (SICCA; http://sicca.ucsf.edu/; HHSN268201300057C) collection. These subjects are part of a larger, 36-subject study group for which blood, gland tissue, and cell-sorted blood samples have been methylotyped (110 samples total). We generated genome-wide DNA methylation profiles using Illumina HumanMethylation450 BeadChips and further characterized full genome SNP profiles using the Illumina HumanOmni2.5-Quad platform. All methylation results were background subtracted via out-of-band normal-exponential convolution (NOOB) and normalized via all sample mean normalization (ASMN) and beta-mixture quantile normalization (BMIQ).

Results

Multidimensional Scaling (MDS) applied to the 360,546 CpG sites passing strict QC criteria visibly separates primary SS cases from controls within the first 2-3 components, and this clustering changes substantially with the inclusion of a subset of 9 symptomatic SICCA control subjects (control status based on SICCA’s extensive clinical and serologic data). We demonstrate significant gene-centered mean hypomethylation across IL10 and IRF5 in SS cases (False Discovery Rate ≤ .05). Mean methylation levels within 15 other putative SS-associated genes were similar between cases and controls. We report median methylation levels in specific BLK and KLHL24 CpGs that are 15-25% hypermethylated in primary SS cases versus controls; other sites in IRF5 and BLK display 10-20% hypomethylation. Single-site methylation differences across 7 of the 17 genes retain significance after multiple-testing correction, with 6 of the 7 genes exhibiting hypomethylation at a majority of sites.

Conclusion

Our results emphasize the utility of DNA methylation as a potential biomarker of disease status. Additional research, including studies of pathway-specific gene expression will be required to fully define the role of DNA methylation in SS-affected salivary glands.

Disclosure:

M. Cole,
None;

X. Shao,
None;

D. Quach,
None;

H. L. Quach,
None;

L. F. Barcellos,
None;

L. A. Criswell,
None.

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