The -174G allele of the interleukin-6 gene confers susceptibility to systemic arthritis in children: a multicenter study using simplex and multiplex juvenile idiopathic arthritis families

Arthritis Rheum. 2003 Nov;48(11):3202-6. doi: 10.1002/art.11300.


Objective: Levels of interleukin-6 (IL-6) have been shown to correlate with the fever and disease activity of systemic juvenile idiopathic arthritis (JIA). In a previous case-control study, a significant association between the IL-6 -174 nucleotide variant and systemic JIA was noted, and HeLa cell transfection assays show functional differences in levels of transcription of the IL-6 -174 alleles. The present study was undertaken to confirm the previous findings and to assess possible association with variations of the A(n)T(n) tract in the promoter.

Methods: We studied a cohort of JIA families from 3 countries, using transmission disequilibrium testing. Genotyping of the -174 nucleotide variant was done by restriction fragment length polymorphism, heteroduplex analysis, or allelic discrimination. The A(n)T(n) tract at -392 to -373 was typed using DNA sequencing. Statistical analysis was performed using the programs Transmit and EHplus.

Results: There was a significant excess transmission of the -174G allele in the systemic JIA families (P = 0.041). The excess transmission was only to systemic JIA patients with age at onset >5 years (P = 0.007). No significant association with the other subtypes was found. No A(n)T(n) alleles or -174/A(n)T(n) haplotypes were significantly associated with systemic JIA.

Conclusion: This study confirms that the IL-6 -174 nucleotide variant is significantly associated with systemic JIA. The significant excess transmission to patients with age at onset >5 years but not to those with age at onset < or =5 years suggests that there may be genetic heterogeneity between the 2 groups.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Alleles*
  • Arthritis, Juvenile / genetics*
  • Arthritis, Juvenile / metabolism
  • Child
  • Child, Preschool
  • DNA / analysis
  • Genetic Predisposition to Disease*
  • Genotype
  • Heteroduplex Analysis
  • Humans
  • Infant
  • Interleukin-6 / genetics*
  • Interleukin-6 / metabolism
  • Linkage Disequilibrium*
  • Polymorphism, Restriction Fragment Length
  • Polymorphism, Single Nucleotide / genetics*
  • Sequence Analysis, DNA


  • Interleukin-6
  • DNA