Genome-wide DNA methylation analysis in multiple tissues in primary Sjogren's syndrome reveals regulatory effects at interferon-induced genes

被引:143
作者
Imgenberg-Kreuz, Juliana [1 ]
Sandling, Johanna K. [1 ,2 ]
Almlof, Jonas Carlsson [1 ]
Nordlund, Jessica [1 ]
Signer, Linnea [2 ]
Norheim, Katrine Braekke [3 ]
Omdal, Roald [3 ]
Ronnblom, Lars [2 ]
Eloranta, Maija-Leena [2 ]
Syvanen, Ann-Christine [1 ]
Nordmark, Gunnel [2 ]
机构
[1] Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Uppsala, Sweden
[2] Uppsala Univ, Dept Med Sci, Rheumatol & Sci Life Lab, SE-75185 Uppsala, Sweden
[3] Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway
基金
瑞典研究理事会;
关键词
NAIVE CD4+T CELLS; MICRORNA EXPRESSION; ASSOCIATION; LYMPHOMA; SYSTEM; LUPUS; RNA; INFLAMMATION; PATHOGENESIS; ACTIVATION;
D O I
10.1136/annrheumdis-2015-208659
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objectives Increasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjogren's Syndrome (pSS). The aim of this study was to investigate the role of DNA methylation in pSS by analysing multiple tissues from patients and controls. Methods Genome-wide DNA methylation profiles were generated using HumanMethylation450K BeadChips for whole blood, CD19+ B cells and minor salivary gland biopsies. Gene expression was analysed in CD19+ B cells by RNA-sequencing. Analysis of genetic regulatory effects on DNA methylation at known pSS risk loci was performed. Results We identified prominent hypomethylation of interferon (IFN)-regulated genes in whole blood and CD19+ B cells, including at the genes MX1, IFI44L and PARP9, replicating previous reports in pSS, as well as identifying a large number of novel associations. Enrichment for genomic overlap with histone marks for enhancer and promoter regions was observed. We showed for the first time that hypomethylation of IFN-regulated genes in pSS B cells was associated with their increased expression. In minor salivary gland biopsies we observed hypomethylation of the IFN-induced gene OAS2. Pathway and disease analysis resulted in enrichment of antigen presentation, IFN signalling and lymphoproliferative disorders. Evidence for genetic control of methylation levels at known pSS risk loci was observed. Conclusions Our study highlights the role of epigenetic regulation of IFN-induced genes in pSS where replication is needed for novel findings. The association with altered gene expression suggests a functional mechanism for differentially methylated CpG sites in pSS aetiology.
引用
收藏
页码:2029 / 2036
页数:8
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