Analysis of Chromatin Data Supports a Role For CD14+ Monocytes/Macrophages in Mediating Genetic Risk for Juvenile Idiopathic Arthritis

Introduction Genome wide association studies (GWAS) have identified multiple regions that confer genetic risk for the polyarticular/oligoarticular forms of juvenile idiopathic arthritis (JIA). However, genome-wide scans do not identify the cells impacted by genetic polymorphisms on the risk haplotypes or the genes impacted by those variants. We have shown that genetic variants driving JIA risk are likely to affect both innate and adaptive immune functions. We provide additional evidence that JIA risk variants impact innate immunity. Materials and Methods We queried publicly available H3K4me1/H3K27ac ChIP-seq data in CD14+ monocytes to determine whether the linkage disequilibrium (LD) blocks incorporating the SNPs that tag JIA risk loci showed enrichment for these epigenetic marks. We also queried monocyte/macrophage GROseq data, a functional readout of active enhancers. We defined the topologically associated domains (TADs) encompassing enhancers on the risk haplotypes and identified genes within those TADs expressed in monocytes. We performed ontology analyses of these genes to identify cellular processes that may be impacted by these variants. We also used whole blood RNAseq data from the Genotype-Tissue Expression (GTEx) data base to determine whether SNPs lying within monocyte GROseq peaks influence plausible target genes within the TADs encompassing the JIA risk haplotypes. Results The LD blocks encompassing the JIA genetic risk regions were enriched for H3K4me1/H3K27ac ChIPseq peaks (p=0.00021 and p=0.022) when compared to genome background. Eleven and sixteen JIA were enriched for resting and activated macrophage GROseq peaks, respectively risk regions (p=0.04385 and p=0.00004). We identified 321 expressed genes within the TADs encompassing the JIA haplotypes in human monocytes. Ontological analysis of these genes showed enrichment for multiple immune functions. Finally, we found that SNPs lying within the GROseq peaks are strongly associated with expression levels of plausible target genes in human whole blood. Conclusions These findings support the idea that both innate and adaptive immunity are impacted by JIA genetic risk variants.