Background/Purpose: The transcriptomes of peripheral blood cells in children with juvenile idiopathic arthritis (JIA) show distinct transcriptional aberrations that suggest impairment of transcriptional regulation. To gain a better understanding of this phenomenon, we studied known JIA genetic risk loci, the majority of which are located in non-coding regions, where transcription is regulated and coordinated on a genome-wide basis.

Methods: We examined the chromatin architecture in human neutrophils and CD4 primary T cells to identify genes and functional elements located within JIA-associated genetic risk loci.We analyzed RNA-Seq data, H3K27ac and H3K4me1 chromatin immunoprecipitation-sequencing (ChIP-Seq) data, and previously published chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) data in CD4+ T cells to gain insights into cellular mechanisms that may contribute to genetic risk in JIA.

Results: In both neutrophils and primary CD4+ T cells, the majority of the JIA-associated linkage disequilibrium (LD) blocks contained H3K27ac and/or H3K4me1 marks. These LD blocks were also binding sites for a small group of transcription factors, particularly in neutrophils. Furthermore, these regions showed abundant intronic and intergenic transcription in neutrophils. In neutrophils, none of the genes that were differentially expressed between untreated JIA patients and healthy children was located within the JIA risk LD blocks. In CD4+ T cells, multiple genes, including HLA-DQA1, HLA-DQB2, TRAF1, and IRF1 were associated with the long-distance interacting regions within the LD regions as determined from ChIA-PET data.

Conclusion: These findings add insight into how genetic risk contributes to the aberrant transcriptional control observed in JIA. Furthermore, the complex chromatin interactions identified here demonstrate the challenges of identifying the actual causal variants within complex genomic/chromatin landscapes.