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Background  The cytokine  IL-10  and its family members have been implicated in autoimmune diseases and we have previously reported that genetic variants in  IL-10  were associated with a rare group of diseases called juvenile idiopathic arthritis (JIA). The aim of this study was to fine map genetic variants within the  IL-10  cytokine family cluster on chromosome 1 using linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (tSNPs) approach with imputation and conditional analysis to test for disease associations.    Methodology/Principal Findings  Fifty-three tSNPs were tested for association between Caucasian paediatric cohorts [219 systemic JIA (sJIA), 187 persistent oligoarticular JIA (pOJIA), and 139 extended OJIA (eOJIA) patients], and controls (Wellcome Trust control cohort, WTCCC2). Significant association with sJIA was detected at rs1400986 in the promoter of  IL-20  (odds ratio 1.53; 95% CI 1.21–1.93; p = 0.0004), but in no other subtypes. Imputation analysis identified additional associated SNPs for pOJIA at  IL-20  and  IL-24 , including a rare, functional, missense variant at  IL-24  with a p = 0.0002. Penalised logistic regression analysis with HyperLasso and conditional analysis identified several further associations with JIA subtypes. In particular, haplotype analysis refined the sJIA association, with a joint effect at rs1400986 and rs4129024 in intron 1 of  MAPKAPK2  (p = 3.2E−5). For pOJIA, a 3-SNP haplotype including rs1878672 in intron 3 of  IL-10  showed evidence for association (p = 0.0018). In eOJIA, rs10863962 (3′UTR of  FCAMR ) and rs12409577 (intron of IL-19) haplotype showed some evidence of association (p = 0.0003).    Conclusions  This study supports previous association of  IL-20  with sJIA. Haplotype analyses provided stronger association signals than single point analyses, while a penalised logistic regression approach also suggested multiple independent association signals. Replication studies are required to confirm or refute these findings. The results indicate that combined effects with unknown/rare variants remain to be characterised in JIA, and represent a possible example of synthetic association in this region.

Association of the IL-10 Gene Family Locus on Chromosome 1 with Juvenile Idiopathic Arthritis (JIA)