Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications

Abstract

Objectives: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA.

Methods: We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes.

Results: The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes.

Conclusions: The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways.

Keywords: Adult Onset Still's Disease; Gene Polymorphism; Juvenile Idiopathic Arthritis.

Figure 1

Genome-wide association results from meta-analysis of nine INCHARGE sJIA collections. The threshold of genome-wide significance (p<2.5×10⁻⁸) is shown by the blue line, while the orange line marks the level of significance suggestive of association (p<5×10⁻⁶). The top 10 sJIA-associated loci are labelled with the name of the nearest gene(s). INCHARGE, International Childhood Arthritis Genetics Consortium; MHC, major histocompatibility complex; sJIA, systemic juvenile idiopathic arthritis.

Figure 2

Systemic juvenile idiopathic arthritis (sJIA) susceptibility locus at chr1p36.32. A regional association plot demonstrates the association between sJIA) and single nucleotide polymorphisms (SNPs) in this region (A). The effect of the peak SNP (rs72632736) in each study population is demonstrated in the forest plot (B). The threshold of genome-wide significance (p<2.5×10⁻⁸) is marked by the black horizontal line in (A) and (C). Panel C shows the superimposition of sJIA-associated SNPs (inset box, A) with transcription factor-binding sites determined by chromatin immunoprecipitation (ChIP) sequencing from the Encyclopedia of Noncoding DNA Elements (ENCODE) project.

Figure 3

Comparison of the genetic architecture of systemic juvenile idiopathic arthritis (sJIA) with seronegative polyarticular and oligoarticular (polygo) JIA. Kernel density plots display the distribution of polygo-wGRS in sJIA cases and controls from the full study collection (A). p Value was calculated with the Wilcoxon rank-sum test. Receiver operator characteristic (ROC) curves with area under the curve (AUC) calculations demonstrate the performance of polygo-wGRS at predicting sJIA status in the full collection (B). Q–Q plots show the level of association of subsets of polygoJIA-associated single nucleotide polymorphisms in the sJIA population (C).