Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Polyarticular juvenile idiopathic arthritis (JIA) is a complex trait characterized by gene-environment interactions. While we are beginning to identify multiple genomic regions associated with disease risk in JIA, most of that risk is located within non-coding regions of the genome. Thus, to develop a mechanistic understanding of how genetic variance contributes to JIA, we require a detailed understanding of the non-coding genome and the functional elements located within these regions.
Methods: We created a multidimensional genomic map in JIA. Using genome-wide methylation sequencing, RNA sequencing, and chromatin immunoprecipitation-sequencing for informative histone marks (H3K4me1 and H3K27ac) in neutrophils, as well as whole genome sequencing on the Illumina 10x platform, we provide new insights into the interaction between genetic variation, the epigenome, and gene expression in the context of a common human disease.
Results: The epigenomes of JIA neutrophils display numerous differences from those from healthy children. DNA methylation changes, however, had only a weak effect on gene expression. In contrast, H3K4me and H3K27ac marks, commonly associated with enhancer functions, strongly correlated with gene expression. Furthermore, although some unique/novel enhancer marks were associated with insertion-deletion events (indels) identified on whole genome sequencing, genetic variation could account for no more than 30% of the JIA-specific epigenome. Treatment with methotrexate was associated with a re-ordering of transcription associated with changes in both methylation and histone marks, including histone and methylation marks located within indels. This finding demonstrates the plasticity of the epigenome in this setting. Alterations in histone marks most strongly associated with the transcriptional changes that accompanied the initiation of therapy.
Conclusion: JIA represents a complex genetic-epigenetic trait characterized by aberrant transcription in pathologically relevant cells. Initiation of effective therapy is associated with significant re-ordering of the epigenome, even in genomic regions where there is underlying genetic variance.
To cite this abstract in AMA style:Jarvis J, Zhu L, Jiang K, Buck M, Chen Y, Moncrieffe H, Brungs L, Liu T, Wang T. A Multi-Dimensional Genomic Map for Polyarticular Juvenile Idiopathic Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/a-multi-dimensional-genomic-map-for-polyarticular-juvenile-idiopathic-arthritis/. Accessed November 28, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-multi-dimensional-genomic-map-for-polyarticular-juvenile-idiopathic-arthritis/