The DNA methylation landscape of CD4+ T cells in oligoarticular juvenile idiopathic arthritis. (January 2018)

• Record Type: Journal Article
• Authors: Chavez-Valencia, Raul A.; Chiaroni-Clarke, Rachel C.; Martino, David J.; Munro, Jane E.; Allen, Roger C.; Akikusa, Jonathan D.; Ponsonby, Anne-Louise; Craig, Jeffrey M.; Saffery, Richard; Ellis, Justine A.
• Is Part Of: Journal of autoimmunity. Volume 86(2018)
• Page Start: 29
• Page End: 38
• Publication Date: 2018-01
• Subjects: Epigenetics -- DNA methylation -- Juvenile idiopathic arthritis -- Autoimmunity -- CD4+ T cells; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2017.09.010
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Juvenile idiopathic arthritis (JIA) is presumed to be driven by an adverse combination of genes and environment. Epigenetic processes, including DNA methylation, act as a conduit through which the environment can regulate gene activity. Altered DNA methylation has been associated with adult autoimmune rheumatic diseases such as rheumatoid arthritis, but studies are lacking for paediatric autoimmune rheumatic diseases including JIA. Here, we performed a genome-scale case-control analysis of CD4 + T cell DNA methylation from 56 oligoarticular JIA (oJIA) cases and 57 age and sex matched controls using Illumina HumanMethylation450 arrays. DNA methylation at each array probe was tested for association with oJIA using RUV (Remove Unwanted Variation) together with a moderated t -test. Further to this 'all-inclusive' analysis, we stratified by age at diagnosis (≤6yrs, >6yrs) and by sex as potential sources of heterogeneity. Following False Discovery Rate (FDR) adjustment, no probes were associated with oJIA in the all-inclusive, >6yrs-diagnosed, or sex-stratified analyses, and only one probe was associated with oJIA in the ≤6yrs-diagnosed analysis. We attempted technical validation and replication of 14 probes (punadj <0.01) at genes of known/potential relevance to disease. At VPS53, we demonstrated a regional shift towards higher methylation in oJIA (all-inclusive) compared to controls. At REEP3, where polymorphism has been previously associated with JIA, we demonstrated higher DNA methylation in male oJIA compared to male controls. This is the most comprehensive JIA case-control analysis of DNA methylation to date. While we have generated some evidence of altered methylation in oJIA, substantial differences are not apparent in CD4 + T cells. This may indicate a lesser relevance of DNA methylation levels in childhood, compared to adult, rheumatic disease. Highlights: No substantial alterations to DNA methylation are apparent in oJIA CD4 + T cells. DNA methylation may play a lesser role in JIA than in rheumatoid arthritis. Modest alterations were detected at genes of known/potential relevance to JIA. Stratifying by diagnosis age or sex appeared to reduce molecular heterogeneity.