ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2100

Hypomethylation in Enhancer and Promoter Regions of Interferon Regulated Genes in Multiple Tissues Is Associated with Primary Sjögren’s Syndrome

Juliana Imgenberg-Kreuz1, Johanna K Sandling1,2, Jonas Carlsson Almlöf1, Jessica Nordlund1, Linnea Signér2, Katrine B Norheim3, Roald Omdal3, Majia-Leena Eloranta2, Lars Rönnblom2, Ann-Christine Syvänen1 and Gunnel Nordmark2, 1Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden, 2Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden, 3Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: , , ,

Session Information

Date: Monday, November 9, 2015

Title: Genetics, Genomics and Proteomics

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose:

Epigenetic modifications have emerged as important contributing factors in the pathogenesis of autoimmune diseases, including primary Sjögren’s syndrome (pSS), and may act as a link between the environment and the genome. The aim of this study was to investigate DNA methylation in multiple tissues and its functional implications for pSS susceptibility.

Methods:

DNA prepared from whole blood samples (patients n=100, controls n=400), positively selected CD19+ B cells (patients n=24, controls n=47) and minor salivary gland biopsies (patients n=15, controls n=13) was analysed on the Illumina HumanMethylation 450k array, covering 485,000 CpG sites across the genome.  Age and sex were included as covariates in the association model and a p-value of <1×10-7 was considered significant (Bonferroni correction). Genomic coordinates of differentially methylated sites were tested for overlap with histone marks in publicly available data from reference B and T cells, and the association of genetic variants in known pSS risk loci with DNA methylation was investigated. In addition, gene expression was analysed by RNA-sequencing in CD19+ B cells from 16 patients and 24 controls.

Results:

We identified prominent hypomethylation in type I interferon regulated genes in whole blood, CD19+ B cells and minor salivary gland biopsies in patients with pSS. Enrichment for genomic overlap of these differentially methylated sites with histone marks of enhancer and promoter regions was observed. Analysis in whole blood from the controls showed that genetic variants located in or close to the pSS risk loci DDX6-CXCR5, FAM167A-BLK, IL12A, IRF5-TNPO3, STAT4, TNIP1, and within the HLA-region were associated with methylation levels at proximal CpG sites. In CD19+ B cells a correlation between hypomethylation and increased gene expression levels was identified for several interferon regulated genes with prominent hypomethylated sites overlapping enhancer regions, these genes included MX1, IFI44L, IFITM1 and RSAD2.

Conclusion:

Our results further emphasize the role of DNA methylation in the pathogenesis of pSS. The importance of genes in the interferon system is highlighted, and the correlation with altered gene expression suggests a potential functional mechanism for differentially methylated CpG sites in pSS.

Disclosure: J. Imgenberg-Kreuz, None; J. K. Sandling, None; J. Carlsson Almlöf, None; J. Nordlund, None; L. Signér, None; K. B. Norheim, None; R. Omdal, None; M. L. Eloranta, None; L. Rönnblom, None; A. C. Syvänen, None; G. Nordmark, None.

To cite this abstract in AMA style:

Imgenberg-Kreuz J, Sandling JK, Carlsson Almlöf J, Nordlund J, Signér L, Norheim KB, Omdal R, Eloranta ML, Rönnblom L, Syvänen AC, Nordmark G. Hypomethylation in Enhancer and Promoter Regions of Interferon Regulated Genes in Multiple Tissues Is Associated with Primary Sjögren’s Syndrome [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/hypomethylation-in-enhancer-and-promoter-regions-of-interferon-regulated-genes-in-multiple-tissues-is-associated-with-primary-sjogrens-syndrome/. Accessed .

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