Emma M Ogilvie1, Mark S Fife1, Susan D Thompson2, Natalie Twine1, Monica Tsoras2, Sheila A Fisher3, Cathryn M Lewis3, Anne-Marie Prieur4, David N Glass2, Pat Woo1
1University College London, London, United Kingdom2Children's Hospital Medical Center, Cincinnati, OH;3Guy's, Kings and St Thomas' School of Medicine, London, United Kingdom4Necker, Paris, France |
Background: IL-6 is a pleiotropic cytokine involved in the regulation of immune cell function and the acute phase response. Patients with Systemic Arthritis (SA), a subgroup of Juvenile Idiopathic Arthritis (JIA), exhibit a rise and fall in IL-6 levels that parallel the classical spiking fever. Furthermore, serum IL-6 levels correlate with disease activity in SA.
We have previously reported a significant deficiency of the IL-6 -174 CC genotype in SA when compared with controls1. Additionally, functional differences in levels of transcription of the IL-6 -174 alleles in HeLa cell transfection assays suggest that this SNP is biologically important. Associations of the IL-6-174 SNP have recently been found with several autoimmune diseases. Our current study used a cohort of 511 simplex JIA families (214 with SA) in a Transmission Disequilibrium Test (TDT) for association to confirm our previous findings.
Methods: Genotyping of all individuals was done by RFLP, heteroduplex analysis, or allelic discrimination on the ABI PRISM 7000 with Taqman® probes. TDT analysis was performed using the programme TRANSMIT.
Results: JIA as a whole showed no association with the IL-6 -174 SNP. Analysis showed significant excess transmission of the -174G allele in the SA subgroup (p=0.05). When subdivided by age at onset (early £5; late >5), late onset patients showed at stronger transmission bias of the -174G allele (p = 0.0008).
Discussion: In part this result confirms our previously reported association of the IL-6 -174 SNP with SA. The excess transmission of the -174G allele is consistent with the under representation of the -174 CC genotype previously found in the case control study, although the age stratification in the present family-based study differs from the case-control (with the bias occurring in the older onset patient group). This supports our hypothesis that the lower expressing CC genotype is protective against systemic JIA since controls with the CC genotype have significantly lower serum levels of IL6.
1. J Clin Invest. (1998) 102: 1369-76
This Work was funded by the Arthritis Research Campaign and by NIAMS (AR47363-02; N01-AR-4-2218). We acknowledge the BPRG study group and the association Kourir for their contributions. |
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