The 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.
Paediatric Rheumatology Unit, Windeyer Institute of Medical Sciences, University College London Medical School, London W1P 6DB.
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D
Fishman
G
G
Faulds
R
R
Jeffery
V
V
Mohamed-Ali
J S
JS
Yudkin
S
S
Humphries
P
P
Woo
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001171:Arthritis, Juvenile / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D001483:Base Sequence; D002648:Child; D017931:DNA Primers; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics*; D008131:London; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012016:Reference Values; D014158:Transcription, Genetic; D014162:Transfection
D017931:DNA Primers; D015850:Interleukin-6