Stock, C.J.W.; (2011) The interleukin 1 gene family in systemic juvenile idiopathic arthritis. Doctoral thesis , UCL (University College London).

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Abstract

Patients with systemic Juvenile Idiopathic Arthritis (sJIA) have elevated serum levels of inflammatory cytokines. Treatment with interleukin-1 (IL-1) receptor antagonist (Anakinra) shows remarkable improvement in some sJIA patients. The hypothesis of this thesis is that genetic variations in IL-1 family genes contribute to disease pathogenesis. To investigate this, a two-stage case-control association study of 20 candidate genes was performed. Selected tagging SNPs were tested for association in 130 sJIA patients and 146 controls in stage-1 of the study. SNPs at significantly different frequencies in the cohorts were genotyped in an additional 105 sJIA patients and 184 controls, and stratified metaanalysis of the two-stage data performed. Analysis was also performed with 4,671 controls from the Wellcome Trust Case Control Consortium (WTCCC). No associations were found with caspase-1, cryopyrin, or IL-18. Significant disease associations were identified with SNPs in the ligand IL1A, the receptor antagonist IL1RN, and a two-SNP haplotype in the IL-18 antagonist IL18BP. Associations were also identified in the decoy receptor IL1R2, and the co-receptor IL1RAP, although these were not confirmed when re-analysed with the WTCCC controls. Transient transfection assays with haplotype constructs, performed by Dr Wen, showed that the IL18BP haplotype affected gene transcription levels in vitro. This effect was not however reproduced using PBMCs from healthy individuals. Allele specific binding to one of the haplotype SNPs was predicted in silico, but no evidence for this was seen in EMSA experiments. Further functional studies are required to corroborate involvement of this haplotype in disease. In summary, this study has identified genetic associations for susceptibility to sJIA with a number of IL1 family members. These results indicate that there may be aberrant control of IL-1 activity in patients with sJIA. Further work is required to determine how these associated SNPs affect IL-1 activity, and thereby the inflammatory response in sJIA.

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