Background/Purpose: Systemic juvenile idiopathic arthritis (sJIA) is a severe inflammatory disease of childhood characterized by periods of daily spiking fever, evanescent skin rash, arthritis, serositis, lymphoid hyperplasia, and in up to half of cases, macrophage activation syndrome. The causes of sJIA are unknown, and the rare nature and complex inheritance of sJIA have together stymied the investigation of sJIA genetics.

Methods: To identify genetic factors contributing to sJIA susceptibility, we generated single nucleotide polymorphism (SNP) genotypes in 988 children with sJIA and 514 healthy control subjects using a commercially available SNP array. These data were combined with SNP genotypes, in silico, from 7370 additional healthy control subjects. After dividing the dataset into 9 strata by country of origin, we excluded samples and markers that failed to meet strict quality standards. Haplotype phasing, SNP imputation, and association testing were performed independently in each stratum, and we then subjected the association results from > 1.6M SNPs to fixed- and random-effects meta-analyses. A second round of more intensive imputation employing a more densely genotyped set of reference haplotypes was performed in each region with p_min < 1.0E-7. Regions with association signals exceeding genomewide significance (p < 1.7E-8) were further evaluated with logistic regression and conditional analysis.

Results: Genome wide meta-analysis of sJIA identified associations between sJIA and two regions, the major histocompatibility complex (MHC) locus and an intergenic region on chromosome 1, each of which were subjected to a second round of SNP imputation. In both regions, meta-analysis of the second round of imputation data identified significant associations. Meta-analyses of the MHC locus identified two strong association signals, the first centered around HLA-DRB1 (p_min = 1.6E-10, OR 1.5) and the second located between BTNL2 and HLA-DRA (p_min = 7.1E-15, OR 2.2). Reciprocal univariate regression demonstrated that these two markers likely represent independent sources of sJIA risk. On chromosome 1, we identified an sJIA-associated cluster of 9 SNPs (p_min = 5.4E-9, OR 2.0) that was nearest to LOC284661, encoding a long, intergenic noncoding RNA. By cross referencing data from the ENCODE project with the 9 sJIA associated SNPs, we found evidence of transcriptional activity across the sJIA-associated region and in close proximity to many of the sJIA-associated SNPs. Furthermore, several of the sJIA-associated SNPs were located within known histone marks or transcription factor binding sites.

Conclusion: Our data implicate the class II MHC molecule, HLA-DR, in the pathogenesis of sJIA. The intergenic location of the most strongly associated variants raises the possibility that an alteration of HLA-DR regulation or expression may underlie its role in sJIA.  Additionally, we have identified a novel genomic region on chromosome 1 as an sJIA susceptibility locus. Interestingly, the nearest gene encodes an uncharacterized long, intergenic noncoding RNA, a type of transcriptional regulator whose importance has only recently come to light.