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(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.


CONCLUSIONS
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.
Ogilvie
Emma M
EM
University College London, London, UK.
Fife
Mark S
MS
Thompson
Susan D
SD
Twine
Natalie
N
Tsoras
Monica
M
Moroldo
Marta
M
Fisher
Sheila A
SA
Lewis
Cathryn M
CM
Prieur
Anne-Marie
AM
Glass
David N
DN
Woo
Patricia
P
D000293:Adolescent; D000483:Alleles; D001171:Arthritis, Juvenile / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000032:analysis; D020022:Genetic Predisposition to Disease; D005838:Genotype; D020180:Heteroduplex Analysis; D006801:Humans; D007223:Infant; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D015810:Linkage Disequilibrium; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017422:Sequence Analysis, DNA
D015850:Interleukin-6; D004247:DNA