Analysis of chromatin data supports a role for CD14+ monocytes/macrophages in mediating genetic risk for juvenile idiopathic arthritis

Abstract

IntroductionGenome 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 methodsWe 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.ResultsThe 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.ConclusionsThese findings support the idea that both innate and adaptive immunity are impacted by JIA genetic risk variants.

Advancements and progress in juvenile idiopathic arthritis: A Review of pathophysiology and treatment

“…[ 43 ] By analyzing protein-coding regions of the genome in JIA patients compared to controls, rare genetic variants affecting immune cell function and inflammatory molecule production have been identified. [ 44 , 45 ] Additionally, copy number variations and structural variations have been detected in JIA patients, which are not captured by GWAS and EHR studies. PheWAS studies have investigated genetic associations with specific JIA subtypes and phenotypic characteristics such as joint involvement and the presence of specific autoantibodies.…”

Shared genomic segments analysis identifies MHC class I and class III molecules as genetic risk factors for juvenile idiopathic arthritis

“…CD4+ T cells are the most frequently implicated cell type in JIA pathophysiology, but the roles of additional immune cell types such as macrophages have also been investigated. 46 To capture a wide array of immune cell types, we utilized the Database of Immune Cell Expression (DICE) to assess expression data for 15 immune cell types and states in genes that lie within genome-wide significant regions. The 2-Mb segment at 12q23.2-q23.3 shared by three distantly related subjects contains the gene DRAM1 , which encodes an autophagy induction protein that is primarily expressed by monocytes.…”

Synovial monocytes contribute to chronic inflammation in childhood-onset arthritis via IL-6/STAT signalling and cell-cell interactions

“…A role of IL-6 in oJIA has been implied decades ago ( 50 ). In addition, a recent study investigating chromatin data in monocytes in JIA patients found that IL-6 binding was one of the top enriched processes ( 21 ). Interestingly, our data showed that the magnitude of IL-6/JAK/STAT activation in monocytes was reflected in the levels of several circulating cytokines.…”