Cited by 2,243Autoimmune and Inflammatory Disorders ResearchCytokine Signaling Pathways and InteractionsGenetic Associations and Epidemiology

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.

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Fishman, D, Faulds, G, Jeffery, R, Mohamed-Ali, V, Yudkin, J S, Humphries, S, Woo, P·1998·Journal of Clinical Investigation

Abstract

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.

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  • These autoimmune diseases are associated with dysregulated production of IL-6 in humans.

    “These autoimmune diseases are associated with dysregulated production of IL-6 in humans (41–43) and impaired activation of the HPA axis in both humans (44) and animal models (1).”

    From Interleukin-6 is an essential, corticotropin-releasing hormone-independent stimulator of the adrenal axis during immune system activation (2000) · cites this paper as [42]

    The Introduction (page unavailable) reports elevated IL-6 in the serum and inflamed joints of patients with juvenile chronic arthritis and describes an unusual cyclical pattern of IL-6 in active systemic-onset disease. This supports dysregulated IL-6 in that human condition, but the paper does not establish the claim for the broader group of autoimmune diseases implied by “these autoimmune diseases.” (LLM, conf=0.85)

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  • The frequency of a polymorphism at the 5' flanking region of the IL-6 gene that is correlated with lower levels of plasma IL-6 is reduced in systemic-onset juvenile chronic arthritis.

    “On the other hand, the frequency of a polymorphism at the 5’ flanking region of the IL-6 gene that is correlated with lower levels of plasma IL-6 is reduced in systemic-onset juvenile chronic arthritis (275).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [275]

    The Abstract reports that the −174C allele is associated with lower plasma IL-6 in healthy subjects. Table IV and the accompanying results report a reduced CC genotype frequency in patients whose arthritis began at age 5 or younger, but no significant reduction in C-allele frequency in any patient group. The claim omits that genotype and age-of-onset qualification. Page numbers are not indicated in our copy. (LLM, conf=0.90)

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Research works printed but not linked: 1

  1. Laxer, R., and R. Schneider. 1993. Systemic-onset juvenile chronic (rheu- matoid) arthritis and adult-onset Still's disease. In Oxford Textbook of Rheu- matology. P. Maddison, D. Isenberg, P. Woo, and D. Glass, editors. Oxford Medical Publications, Oxford. 722-731.

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Authors
Fishman, D., Faulds, G., Jeffery, R., Mohamed-Ali, V, Yudkin, J. S., Humphries, S., & Woo, P.
Affiliations
  • University College London (GB)
  • Whittington Hospital (GB)
Corresponding author
Woo, P
Venue
Journal of Clinical Investigation
Published
1998-10-01
Volume
102
Issue
7
Pages
1369-1376
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2089022749
Cited by
2,243
References
47
Citations by year
2026: 25 · 2025: 21 · 2024: 36 · 2023: 39 · 2022: 57 · 2021: 49 · 2020: 64 · 2019: 61 · 2018: 63 · 2017: 65 · 2016: 96 · 2015: 84 · 2014: 100 · 2013: 123 · 2012: 102
FWCI
24.28
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • British Heart Foundation
  • University of Manchester
  • Medical Research Council
Topics
  • Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
interleukin-6, IL-6 gene polymorphism, 5'-flanking region, genetic association, age of onset, atherosclerosis
MeSH terms
Adolescent, Adult, Aged, Arthritis, Juvenile, Base Sequence, Child, Female, Gene Expression Regulation, Gene Frequency, Genotype, HeLa Cells, Humans, London, Male, Middle Aged, Molecular Sequence Data, Polymorphism, Genetic, Reference Values, Transcription, Genetic, Transfection, Interleukin-6, Polymerase Chain Reaction, Age of Onset, DNA Primers

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