Background/Purpose: Epigenetic regulation of gene expression is increasingly under scrutiny to understand the pathogenesis of multifactorial human diseases, such as juvenile idiopathic arthritis (JIA). Indeed, the low concordance rate between monozygotic twins (20-40%) underscores that, while this autoimmune disease has a genetic component, environmental triggers are fundamental in the disease pathogenesis. Epigenetic mechanisms are believed to integrate such non-genetic factors, and may underlie the dysregulation of the immune system.

Methods: We interrogated the DNA methylome of JIA patients before and after anti-TNF therapy withdrawal with the Infinium HumanMethylation450 BeadChip. Patients were stratified by clinical activity 8 months after withdrawal.

Results: Individual CpG sites were clustered in coherent modules without any a priori knowledge of their function. Strikingly, modules statistically associated with clinical activity were enriched in CpG sites belonging to genes that mediate T cell activation. Conversely, modules linked to age or gender controlled fundamental, non-immune functions of the cell, such as metabolism. Of note, the DNA methylome was stable, showing little variation before and after therapy discontinuation. When a similar analysis was performed on matched transcriptomic data, we found that the correlation of mRNA abundances with clinical activity was much lower than that observed for DNA methylation.

Conclusion: Our work (i) demonstrates that medically relevant information is encoded in epigenetic traits; (ii) reveals biological functions tied to clinical activity; and (iii) establishes the superiority of epigenetic markers over gene expression-based markers.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/epigenetic-traits-correlate-with-clinical-activity-in-juvenile-idiopathic-arthritis/