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

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 _nT_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_nT_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_nT_n alleles or -174/A_nT_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 ≤5:55 years suggests that there may be genetic heterogeneity between the 2 groups.