Interleukin-6 Polymorphisms and 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 9 flanking region of the IL-6 gene for polymorphisms. A G/C polymorphism was detected at position 2 174. 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 9 flanking region ( 2 550– 1 61 bp) in a luciferase reporter vector transiently transfected into HeLa cells, the 2 174C construct showed 0.624 6 0.15-fold lower expression than the 2 174G construct. After stimulation with LPS or IL-1, expression from the 2 174C construct did not significantly change after 24 h, whereas expression from the 2 174G construct increased by 2.35 6 0.10and 3.60 6 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. ( J. Clin. Invest. 1998. 102:1369–1376.)