Chromatin Landscapes and Genetic Risk For Juvenile Idiopathic Arthritis

Abstract

Juvenile idiopathic arthritis (JIA) is considered to be an autoimmune disease mediated by interactions between genes and the environment. To gain a better understanding of the cellular basis for genetic risk, we studied known JIA genetic risk loci, the majority of which are located in non-coding regions, in human neutrophils and CD4 primary T cells to identify genes and functional elements located within those 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 to characterize the chromatin landscapes within the know JIA-associated risk loci. In both neutrophils and primary CD4+ T cells, the majority of the JIA-associated 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. These findings suggest that aberrant transcriptional control is the underlying pathogenic mechanism in JIA. Furthermore, these findings demonstrate the challenges of identifying the actual causal variants within complex genomic/chromatin landscapes.