Background/Purpose: Systemic juvenile idiopathic arthritis (sJIA) is a severe, potentially lethal inflammatory condition. It accounts for a disproportionate share of morbidity and mortality among childhood arthritidies.  Despite recognition of excessive innate immune activation, specific host or environmental factors that underlie sJIA have eluded detection.  Genomic investigations are an important tool for identifying new disease associated genes and pathways, and recent genomic studies of sJIA have yielded important new insights.  Here, we examine sJIA with the Immunochip, a single nucleotide polymorphism (SNP) array that generates exceptionally dense genotyping at 186 immunogenetic loci, many of which are putatively relevant to sJIA.

Methods: Immunochip genotype data were generated in 889 sJIA cases from the International Childhood Arthritis Genetics Consortium and the Juvenile Arthritis Consortium for Immunochip and 16,144 geographically-matched control subjects.  All cases fulfilled the ILAR criteria for sJIA. Genotyping/genotype calling were performed according to the manufacturer’s protocols. The dataset was subjected to stringent quality control operations (QC) to exclude poor quality samples and markers. The study population was systematically restricted to subjects of northern European ancestry using principal components analysis (PCA). The full dataset was expanded with 1000 Genomes Project (1KG)-based SNP imputation.  Haplotypic analysis was performed for novel risk loci and association testing of markers and haplotypes was performed by logistic regression, corrected for sex and ancestry.  The effect of sJIA-associated variables on gene expression was examined in paired whole genome (WGS) and RNA sequencing data from lymphoblastoid cell lines (LCL) of 373 European 1KG subjects.

Results: SNP genotyping, imputation and QC produced a panel of 841,043 SNPs in a collection 579 sJIA cases and 12,930 healthy subjects of northern European ancestry (λGC=1.000). Association testing identified a novel, highly-significant susceptibility locus on chromosome 2 that contained CXCR4, encoding C-X-C chemokine receptor type 4. The strongest risk factor for sJIA in the study was a 124kb 6-SNP haplotype (case frequency 0.21, control frequency 0.13, p=4.3E-10, OR=1.7 [1.5, 1.9]). Analysis of paired WGS and RNAseq data identified positive correlation between the sJIA risk haplotype and CXCR4 expression in LCLs (p=4.0E-4).  Examination of the risk haplotype in public databases revealed that it 1) intersects with a lymphocyte super-enhancer that regulates CXCR4; and 2) engages in 3 distinct chromatin loops with the promoter of CXCR4 in LCLs.

Conclusion: This study has identified CXCR4 as a novel risk locus in sJIA. CXCR4 is an immunologically important molecule that is involved immune cell development and migration, particularly that of B lymphocytes.  The correlation of the sJIA risk haplotype with increased CXCR4 expression in LCLs, its intersection with a lymphocyte-specific super-enhancer and its formation of chromatin loops with the CXCR4 promoter in LCLs may indicate that this haplotype influences sJIA risk through B lymphocytes.  Further studies are necessary to systematically evaluate this hypothesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dense-genotyping-of-immunologic-loci-identifies-cxcr4-as-a-novel-susceptibility-locus-for-systemic-juvenile-idiopathic-arthritis/