Background/Purpose: We have found extensive alterations in chromatin accessibility when the CD4+ T cells of children with active polyarticular juvenile idiopathic arthritis (JIA) are compared with cells from healthy children (HC). These differences in chromatin accessibility are strongly linked to differences in transcription. We therefore sought to determine the extent to which chromatin re-organization in JIA CD4+ T cells is influenced by underlying genetic variation.

Methods: Using our previously published whole genome sequencing data from 48 JIA patients, we identified common SNPs that: (1) were found in all JIA patients and (2) had not been identified previously. We categorized the SNPs as loss (LoF) or gain of function (GoF), based on their likely contributions to the regulatory network of CD4+ T cells, using ATAC-seq data to identify regulatory sequences. Using data from the 1000 genomes project, we identified the SNPs that were in linkage disequilibrium with our predicted LoF and GoF SNPs to identify a set of haplotype blocks. Using data from the ENCODE and RoadMap epigenomics projects, we looked for statistical enrichment for informative histone modifications in myeloid and lymphoid cell lines within these haplotype blocks.

Results:

Results Each of the queried cell lines showed significant enrichment for specific histone marks within the haplotypes of interest. However, findings were most significant within CD4+ T cell subsets, and specifically for histone marks regulating chromatin accessibility. For example, H3K9me3 is a histone mark that is required to maintain chromatin in a condensed state and maintain the identity of terminally differentiated cells. Regions associated with predicted loss of function SNPs were highly enriched for H3K9me3 in CD3+ (p=7.13E-81), CD4+ (p=7.11E-23) and CD8+ T (p=9.67E-37) cell subsets. Predicted gain of function regions were enriched for H3K4me1 marks, an epigenetic signature of poised enhancer function.

Conclusion: We identified novel, predicted genetic risk loci for JIA and identified a strong enrichment for H3K9me3 in T cell subsets. This enrichment was much stronger for regions predicted to be loss of function compared to gain of function. We hypothesize that these genetic variants may alter H3K9me3 localization in JIA, altering the chromatin landscape and leading to the misregulation of transcription.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/juvenile-arthritis-associated-single-nucleotide-polymorphisms-identified-on-whole-genome-sequencing-show-enrichment-within-h3k9me3-marked-regions/