There is now strong evidence supporting the hypothesis of common autoimmune genetic susceptibility loci 1 . Ankylosing spondylitis (AS), psoriasis (Ps) and psoriatic arthritis (PsA) are a group of autoimmune diseases which share some clinical features and some overlapping susceptibility loci such as endoplasmic reticulum aminopeptidase 1 (ERAP1) (formerly known as ARTS1) 2 3 and the interleukin 23 receptor (IL23R) 2 4 5 .

Juvenile idiopathic arthritis (JIA) is an umbrella term for all chronic childhood arthropathies and can be classified into seven subtypes on the basis of features present in the first six months of disease 6 . It includes the enthesitis related arthritis (ERA) subtype, which displays symptoms similar to AS and juvenile onset psoriatic arthritis, which has similarities to psoriatic arthritis and psoriasis. We have, therefore, hypothesized that the two well-established susceptibility loci, ERAP1 and IL23R, also confer susceptibility to these JIA subtypes. To this end the most associated single nucleotide polymorphism (SNP) within each of these genes has been selected for genotyping across all JIA and also analysed stratified by ILAR subtype.

SNPs were in Hardy-Weinberg equilibrium (P > 0.05) in the control cohort.

Neither rs30187 in ERAP1 nor rs11209026 in IL23R were significantly associated with the total JIA dataset (P trend = 0.73, OR = 1.03 95% CI 0.92 to 1.14 and P trend = 0.46, OR = 0.93 95% CI 0.78 to 1.12, respectively).

After stratification by ILAR subtype (Table 1) the ERA subtype showed strong association with the ERAP1 SNP (P trend = 0.005, OR = 1.69 95% CI 1.17 to 2.44). For the IL23R SNP there was significant association in the psoriatic arthritis subtype (P trend = 0.04, OR = 0.4 95% CI 0.16 to 0.98) and a trend towards association in the enthesitis related subtype (P trend = 0.15, OR = 0.52 95% CI 0.21 to 1.28). For both SNPs the association is in the same direction as in the original studies.

Investigating the genetic susceptibility loci identified for clinically related autoimmune diseases has been a very successful strategy in the search for novel JIA susceptibility loci 7 . Using this approach in this study we have identified subtype specific effects in JIA.

We found strong association of the ERA subtype with the ERAP1 SNP. There was no significant association with any other subtype. However, it should be noted that the individual subtypes had between 16 and 54% power to detect an association. The ERAP1 variant, rs30187, is a non-synonymous SNP, K528R, located in exon 6 of the gene previously associated with AS 2 , with Ps 3 and PsA (personal communication, Anne Barton), and also with type 1 diabetes 13 . In a recent fine-mapping study, multiple SNPs across the region were associated with AS and they were not able to identify the causal marker from the genetic data due to the high LD across the region. Imputation analysis in this dataset found strong associations for imputed SNPs, including some SNPs in regulatory regions which may be good candidates for the causal SNP. Further studies on how these SNPs affect expression of ERAP1 are now required 11 .

ERAP1 encodes a multifunctional aminopeptidase, but its role in the pathogenesis in any of the associated diseases has yet to be determined (reviewed in 14 ). It may play a role in trimming peptides, in the endoplasmic reticulum, for binding to HLA class I molecules where they are transported to the cell surface for presentation to T cells. Alternatively it may be important through its function in cleaving pro-inflammatory cytokine receptors, such as tumour necrosis factor receptor 1 (TNFR1) to generate soluble TNFR1. It is also thought to play a role in the cleavage of interleukin 1 receptor 2 (IL1R2) and interleukin 6 receptor alpha (IL6Rα), leading to increased soluble IL1R2 and IL6Rα.

The IL23R SNP showed significant association in the PsA subtype and a trend towards association in the ERA subtype, with similar effect sizes in both subtypes, suggesting that the lack of significant association in the ERA subtype of JIA may just be due to a lack of power (this subtype had 37% power to detect an association). IL23R shows association not only with AS, Ps, PsA 2 4 5 , but also with inflammatory bowel disease 15 and paediatric Crohn's disease 16 . The SNP rs11209026 appears to be the primary associated polymorphism 17 . It is a non-synonymous SNP, Q381R, located in exon 5 of the gene. In all cases the minor allele is associated with protection for developing the disease. The association of IL23R with these conditions suggests that the T Helper 17 (TH17) pathway may be involved in disease pathogenesis. IL23R is also expressed on other immunological cell types such as macrophages, natural killer cells and microglia and it is not yet determined which cell type is affected by the IL23R variant. Therapeutic approaches to inhibiting TH17 cells are now being investigated that could be useful in the treatment of juvenile-onset PsA and the ERA subtype of JIA.

To date it has been very difficult to identify ILAR subtype specific effects in JIA due to small sample sizes and the inevitable loss of power that this entails as well as the issues of multiple testing. In this case there was a strong prior hypothesis that ERAP1 and IL23R confer susceptibility to particular subtypes. However, the results will require validation in independent datasets. The lack of association across the other subtypes will also require further investigation. For the ERAP1 SNP we had between 16 and 54% power to detect an association across the subtypes and for the IL23R SNP we had between 37 and 95% power to detect an association. The search for subtype specific effects in JIA is imperative because it will aid in the refinement of the JIA classification, potentially lead to a better understanding of subtype specific disease pathogenesis, and ultimately to the development of more targeted therapies for the specific subtypes of JIA. It may also be relevant for evaluating prognosis. Not all children with ERA will go on to have the complete AS phenotype and it may be that carriage of these risk alleles predict progression to axial involvement and eventual ankylosis 18 .

We present evidence for subtype specific association of the IL23R gene with juvenile-onset PsA and ERAP1 gene with the ERA subtype of JIA. These results suggest distinct pathogenic pathways in these subtypes.

AS: ankylosing spondylitis; CI: Confidence interval; EGA: European Genome-phenome Archive; ERA: enthesitis related arthritis; ERAP1: endoplasmic reticulum aminopeptidase 1; HWE: Hardy-Weinberg equilibrium; IL1R2: interleukin 1 receptor 2; IL6Rα: interleukin 6 receptor alpha; IL23R: interleukin 23 receptor; ILAR: International League of Associations for Rheumatology; JIA: juvenile idiopathic arthritis; OR: odds ratio; PsA: psoriatic arthritis; Ps: psoriasis; SNP: single nucleotide polymorphism; TH17: T helper 17; TNFR1: tumour necrosis factor receptor 1; WTCCC2: Wellcome Trust Case Control Consortium 2.

The authors declare that they have no competing interests.

AH, WT, SE, JW and AB conceived the study. PM and EF performed the genotyping; AH undertook the statistical analysis. JP, CAPs and the BSPAR study group consortia provided samples. AH, WT and AB drafted the manuscript and all authors contributed to and approved the final version.