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Effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6
transcription and plasma IL-6 levels, and an association with
systemic-onset juvenile chronic arthritis.

During active disease, patients with systemic-onset juvenile chronic
arthritis (S-JCA) demonstrate a rise and fall in serum interleukin-6
(IL-6) that parallels the classic quotidian fever.

To investigate the possibility that this cytokine profile results from
a difference in the control of IL-6 expression, we examined the 5'
flanking region of the IL-6 gene for polymorphisms. A G/C polymorphism
was detected at position -174. In a group of 383 healthy men and women
from a general practice in North London, the frequency of the C allele
was 0.403 (95% confidence interval 0.37-0.44). In comparison, 92
patients with S-JCA had a different overall genotype frequency,
especially those with onset of disease at < 5 yr of age. This was mainly
due to the statistically significant lower frequency of the CC genotype
in this subgroup. When comparing constructs of the 5' flanking region
(-550-+61 bp) in a luciferase reporter vector transiently transfected
into HeLa cells, the -174C construct showed 0.624+/-0.15-fold lower
expression than the -174G construct. After stimulation with LPS or IL-1,
expression from the -174C construct did not significantly change after
24 h, whereas expression from the -174G construct increased by
2.35+/-0.10- and 3.60+/-0.26-fold, respectively, compared with the
unstimulated level. Plasma levels of IL-6 were also measured in 102 of
the healthy subjects, and the C allele was found to be associated with
significantly lower levels of plasma IL-6.

These results suggest that there is a genetically determined difference
in the degree of the IL-6 response to stressful stimuli between
individuals. The reduced frequency of the potentially protective CC
genotype in young S-JCA patients may contribute to its pathogenesis.
Similarly the individual's IL-6 genotype may be highly relevant in other
conditions where IL-6 has been implicated, such as atherosclerosis.

Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S,
Woo P---Paediatric Rheumatology Unit, Windeyer Institute of Medical
Sciences, University College London Medical School, London W1P 6DB.

PMID: 9769329, UI: 98443227


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