Emma M. Ogilvie

Comprehensive association study of genetic variants in the IL-1 gene family in systemic juvenile idiopathic arthritis

Patients with systemic juvenile idiopathic arthritis (sJIA) have a characteristic daily spiking fever and elevated levels of inflammatory cytokines. Members of the interleukin-1 (IL-1) gene family have been implicated in various inflammatory and autoimmune diseases, and treatment with the IL-1 receptor antagonist, Anakinra, shows remarkable improvement in some patients. This work describes the most comprehensive investigation to date of the involvement of the IL-1 gene family in sJIA. A two-stage case–control association study was performed to investigate the two clusters of IL-1 family genes using a tagging single nucleotide polymorphism (SNP) approach. Genotyping data of 130 sJIA patients and 151 controls from stage 1 highlighted eight SNPs in the IL1 ligand cluster region and two SNPs in the IL1 receptor cluster region as showing a significant frequency difference between the populations. These 10 SNPs were typed in an additional 105 sJIA patients and 184 controls in stage 2. Meta-analysis of the genotypes from both stages showed that three IL1 ligand cluster SNPs (rs6712572, rs2071374 and rs1688075) and one IL1 receptor cluster SNP (rs12712122) show evidence of significant association with sJIA. These results indicate that there may be aberrant control of the activity of the IL-1 family in sJIA patients causing the increased susceptibility to the disease.

Novel IL-6 haplotypes and disease association

Interleukin-6 (IL-6) is a pleiotropic cytokine crucial in both adaptive and innate immunity. Numerous genetic studies have shown association with variants of this gene in a multitude of diseases and phenotypes. Most tests of association have focused on a limited set of promoter polymorphisms, in particular, the −174G>C; however, there are many inconsistencies within and between these studies. We propose that there is a more complex regulatory haplotype extending further upstream of the previously characterised promoter region which will provide a more detailed view of the effect of variation on lL-6 regulation. We have exploited two additional single nucleotide polymorphisms (SNPs) in IL-6 that, when examined as a haplotype with existing markers, show an increased level of association with systemic onset juvenile arthritis in a family-based study. This suggests that the haplotype effect may be more functionally relevant to the disease.

Gene expression in active systemic JIA after anti-IL1 and anti-IL6R treatment

We have previously found specific genes upregulated in PBMCs of active sJIA [1]. Biologics to block IL-1 and IL-6 signalling have both been shown to be effective in early clinical trials. In this study we examine the expression before and after anti-IL1 and anti IL-6R treatment in PBMCs and their constitutive cell types; using gene expression analysis to further understand the disease pathways.

Are genetic variants of Caspase-1 and Cryopyrin associated with systemic JIA?

Background The systemic subtype of juvenile idiopathic arthritis (sJIA) can be the most severe, and unlike other forms of JIA is an autoinflammatory disease. There is evidence for the involvement of IL-1 in sJIA: treatment with the IL-1 receptor agonist, Anakinra, has shown dramatic improvement in some sJIA patients. Additionally we have shown a significant association with members of the IL-1 gene family and sJIA [1]. Caspase-1 is required to cleave IL-1β into its active form and Cryopyrin (NLRP3) is part if the IL-1β inflammasome, required for the activation of caspase-1. Mutations in NLRP3 have been found in patients that have similar clinical features with sJIA, e.g. CINCA. Here we describe a candidate gene association study of CASP1 and NLRP3 in sJIA.