Novel IL-10 gene family associations with systemic juvenile idiopathic arthritis (SJIA)

Juvenile idiopathic arthritis (JIA) is the most common cause of chronic childhood disability and encompasses a number of disease subgroups. In this study we have focused on systemic JIA (sJIA), which accounts for approximately 11% of UK JIA cases. This study reports the investigation of three members of the IL10 gene family as candidate susceptibility loci in children with sJIA. DNA from 473 unaffected controls and 172 patients with sJIA was genotyped for a single nucleotide polymorphism (SNP) in IL19 and IL20 and two SNPs in IL10. We examined evidence for association of the four SNPs by single marker and haplotype analysis. Significant differences in allele frequency were observed between cases and controls, for both IL10-1082 (p = 0.031) and IL20-468 (p = 0.028). Furthermore, examination of the haplotypes of IL10-1082 and IL20-468 revealed greater evidence for association (global p = 0.0006). This study demonstrates a significant increased prevalence of the low expressing IL10-1082 genotype in patients with sJIA. In addition, we show a separate association with an IL20 polymorphism, and the IL10-1082A/IL20-468T haplotype. The two marker 'A-T' haplotype confers an odds ratio of 2.24 for sJIA. This positive association suggests an important role for these cytokines in sJIA pathogenesis. Introduction Juvenile idiopathic arthritis (JIA) is the most common cause of childhood disability, with an incidence of 1 in 10 000 children under the age of 16 [1]. It is a clinically heterogeneous group of complex diseases, with polygenic and environmental factors all playing a role in aetiology. There are seven clinically distinct subtypes of JIA [2]. The most severe and least responsive to current therapies is systemic JIA (sJIA), a disease defined by a quotidian fever and one or more manifestations, including an evanescent rash, lymphadenopathy, hepatomegaly or splenomegaly, or serositis. While HLA associations are a significant genetic factor in other JIA subtypes, there are no associations with Caucasian sJIA [3]. However, a number of nonHLA genes have been reported to be associated with sJIA, including those encoding IL6 and Macrophage inhibitory factor [4,5]. IL10 is a cytokine with potent immunoregulatory and antiinflammatory properties. It acts to suppress the release and function of a number of pro-inflammatory cytokines, including IL1, tumour necrosis factor (TNF)-α, and IL6 [6]. Low levels of IL10 production associated with autoimmune disease, such as rheumatoid arthritis, psoriasis, and collagen-induced arthritis, suggest defective regulatory roles of IL10 in limiting inflammation and reversing immunopathology. However, IL10 is also a stimulatory factor for mast cells, B cells, and thymocytes [7,8]. In the upstream regulatory region of the gene encoding IL10, the three most characterised single nucleotide polymorphisms (SNPs) are at positions -1,082 (G to A), -819 (C to T) and 592 (C to A) [9,10]. There is absolute linkage disequilibrium (LD) between the IL10-819 and IL10-592 SNPs. In the Caucasian populations only three out of the remaining four possible haplotypes occur: GCC, ACC and ATA. We have